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STUDY QUESTION: Are there common mutation profiles between epithelial and stromal cells in ovarian endometriotic tissue and the normal endometrium? SUMMARY ANSWER: Our study revealed no common mutations between epithelial and stromal cells in ovarian endometriotic tissue and the normal endometrium. WHAT IS KNOWN ALREADY: Epithelial cells in both ovarian endometriotic tissue and the normal endometrium harbor somatic mutations in cancer-associated genes such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and KRAS proto-oncogene, GTPase (KRAS). STUDY DESIGN, SIZE, DURATION: We performed a retrospective study to identify the mutation profiles of stromal cells in endometriotic tissue and the normal endometrium. We collected 11 endometriotic stroma samples and 10 normal endometrial stroma samples between 2013 and 2017 at a tertiary care center. PARTICIPANTS/MATERIALS, SETTING, METHODS: The laser microdissection method was used to obtain stromal cells in ovarian endometriotic and normal endometrial tissues from patients with ovarian endometriosis and/or other non-invasive gynecological diseases. Target gene sequencing was performed to assess and compare the mutation profiles of stromal cells with those of epithelial cells obtained in our previous study. For target gene sequencing, 76 genes were selected based on previous genomic analyses for ovarian endometriosis, normal endometrium, endometriosis-related ovarian cancer and endometrial cancer. MAIN RESULTS AND THE ROLE OF CHANCE: Stromal samples in ovarian endometrioma and normal endometrium harbor somatic mutations (18 mutations in 11 endometriosis samples and 16 mutations in 10 normal endometrial samples) but did not share any mutations with paired epithelial samples. The mutant allele frequency of stromal samples was significantly lower than that of epithelial samples in ovarian endometrioma (P = 6.0 × 10-11) and normal endometrium (P = 1.4 × 10-7). LIMITATIONS, REASONS FOR CAUTION: The number of genes evaluated in the mutational analysis was limited. Additionally, the functional roles of somatic mutations in stromal cells remain unclear. WIDER IMPLICATIONS OF THE FINDINGS: Different mutation profiles between paired epithelial and stromal cells in both ovarian endometrioma and normal endometrium suggest that origins of epithelial and stromal cells would be independent of each other in both normal endometrium and ovarian endometrioma; however, the theory of epithelial-mesenchymal transition is proposed in ovarian endometrioma. STUDY FUNDING/COMPETING INTEREST(S): This work was supported in part by the Japan Society for the Promotion of Science KAKENHI grant number JP15H02373 (Grant-in-Aid for Scientific Research A for I.I.), JP16H06267 (Grant-in-Aid for Young Scientists A for K.Y.), JP17K08688 (Grant-in-Aid for Scientific Research C for H.N.) and JP16H06279 (Grant-in-Aid for Scientific Research on Innovative Areas-Platforms for Advanced Technologies and Research Resources for H.N. and K.Y). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable.

DOI： 10.1093/humrep/dez155

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INTRODUCTION: BRCA gene mutations are associated with hereditary ovarian cancer. BRCA plays a key role in genome integrity, and mutations result in an increased risk for ovarian cancer. Although various guidelines recommend BRCA testing in patients with ovarian cancer, data on germline BRCA (gBRCA) mutation frequency in ovarian cancer in Japan are scarce. OBJECTIVE: This study aimed to determine gBRCA1/2 mutations in Japanese patients with ovarian cancer, stratified by clinicopathological characteristics, and to assess patients' satisfaction with pre-test genetic counseling. METHODS: The CHARLOTTE study (CHARacterizing the cross-sectionaL approach to Ovarian cancer: geneTic TEsting of BRCA; UMIN000025597) is the first large multicenter epidemiological survey of Japanese women, aged ≥20, with newly diagnosed ovarian cancer (epithelial, primary peritoneal, or fallopian tube cancer), with histologically confirmed specimens. Patients were enrolled sequentially and underwent pre-test genetic counseling for BRCA testing. Blood samples were centrally tested for the presence or absence of known gBRCA mutations. A questionnaire was used to assess patient satisfaction with pre-test genetic counseling. RESULTS: A total of 634 patients with a mean age of 56.9 years were included. Most patients (84.2%) had epithelial ovarian cancer, and 51.1% had FIGO stage III-IV cancer. Nearly all patients (99.5%) received genetic counseling before the BRCA testing, either by an obstetrician-gynecologist (42.0%) or a clinical geneticist (42.0%). The overall prevalence of gBRCA1/2 mutations was 14.7% (93/634), with gBRCA1 mutations (9.9%) more common than gBRCA2 mutations (4.7%). High-grade serous carcinoma showed a prevalence of gBRCA mutations of 28.5%. Most patients were satisfied with pre-test counseling, irrespective of the service provider's professional position. DISCUSSION: Patients with high-grade serous carcinoma and family history of ovarian cancer had a slightly higher prevalence of gBRCA mutations, but none of the subgroups had considerably high gBRCA mutation prevalence. These data suggest that gBRCA testing should be carried out in all patients with ovarian cancer.

DOI： 10.1136/ijgc-2019-000384

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Endometriosis is characterized by ectopic endometrial-like epithelium and stroma, of which molecular characteristics remain to be fully elucidated. We sequenced 107 ovarian endometriotic and 82 normal uterine endometrial epithelium samples isolated by laser microdissection. In both endometriotic and normal epithelium samples, numerous somatic mutations were identified within genes frequently mutated in endometriosis-associated ovarian cancers. KRAS is frequently mutated in endometriotic epithelium, with a higher mutant allele frequency (MAF) accompanied by arm-level allelic imbalances. Analyses of MAF, combined with multiregional sequencing, illuminated spatiotemporal evolution of the endometriosis and uterine endometrium genomes. We sequenced 109 single endometrial glands and found that each gland carried distinct cancer-associated mutations, demonstrating the heterogeneity of the genomic architecture of endometrial epithelium. Remarkable increases in MAF of mutations in cancer-associated genes in endometriotic epithelium suggest retrograde flow of endometrial cells already harboring cancer-associated mutations, with selective advantages at ectopic sites, leading to the development of endometriosis.

DOI： 10.1016/j.celrep.2018.07.037

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Nature  

We previously found that therapeutic targetable fusions are detected across various cancers. To identify therapeutic targetable fusion in uterine cervical cancer, for which no effective gene targeted therapy has yet been clinically applied, we analyzed RNA sequencing data from 306 cervical cancer samples. We detected 445 high confidence fusion transcripts and identified four samples that harbored FGFR3-TACC3 fusion as an attractive therapeutic target. The frequency of FGFR3-TACC3-fusion-positive cervical cancer is also 1.9% (2/103) in an independent cohort. Continuous expression of the FGFR3-TACC3 fusion transcript and protein induced anchorage-independent growth in the cervical epithelial cell line established from the ectocervix (Ect1/E6E7) but not in that from endocervix (End1/E6E7). Injection of FGFR3-TACC3 fusion-transfected-Ect1/E6E7 cells subcutaneously into NOG mice generated squamous cell carcinoma xenograft tumors, suggesting the association between FGFR3-TACC3 fusion and squamous cell carcinogenesis. Transfection of a FGFR3-TACC3 fusion transcript into four cervical cancer cell lines (SiHa, ME180, HeLa, and Ca Ski) induced activation of the MAPK pathway and enhancement of cell proliferation. Transcriptome analysis of the FGFR3-TACC3 fusion-transfected cell lines revealed that an IL8-triggered inflammatory response was increased, via activation of FGFR3-MAPK signaling. Continuous expression of FGFR3-TACC3 fusion led to activation of the PI3K-AKT pathway only in the two cell lines that harbored PIK3CA mutations. Sensitivity to the FGFR inhibitor, BGJ398, was found to depend on PIK3CA mutation status. Dual inhibition of both FGFR and AKT showed an obvious synergistic effect in cell lines that harbor mutant PIK3CA. Additionally, TACC3 inhibitor, KHS101, suppressed FGFR3-TACC3 fusion protein expression and showed antitumor effect against FGFR3-TACC3 fusion-transfected cell lines. FGFR3-TACC3 fusion-positive cancer has frequent genetic alterations of the PI3K/AKT pathway and selection of appropriate treatment based on PI3K/AKT pathway status should be required.

DOI： 10.1038/s41389-017-0018-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press  

Gene fusion represents a class of molecular aberrations in cancer and has been exploited for therapeutic purposes. In this paper we describe TumorFusions, a data portal that catalogues 20 731 gene fusions detected in 9966 well characterized cancer samples and 648 normal specimens from The Cancer Genome Atlas (TCGA). The portal spans 33 cancer types in TCGA. Fusion transcripts were identified via a uniform pipeline, including filtering against a list of 3838 transcript fusions detected in a panel of 648 non-neoplastic samples. Fusions were mapped to somatic DNA rearrangements identified using whole genome sequencing data from 561 cancer samples as a means of validation. We observed that 65% of transcript fusions were associated with a chromosomal alteration, which is annotated in the portal. Other features of the portal include links to SNP array-based copy number levels and mutational patterns, exon and transcript level expressions of the partner genes, and a network-based centrality score for prioritizing functional fusions. Our portal aims to be a broadly applicable and user friendly resource for cancer gene annotation and is publicly available at http://www.tumorfusions.org.

DOI： 10.1093/nar/gkx1018

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Transcript fusions as a result of chromosomal rearrangements have been a focus of attention in cancer as they provide attractive therapeutic targets. To identify novel fusion transcripts with the potential to be exploited therapeutically, we analyzed RNA sequencing, DNA copy number and gene mutation data from 4366 primary tumor samples. To avoid false positives, we implemented stringent quality criteria that included filtering of fusions detected in RNAseq data from 364 normal tissue samples. Our analysis identified 7887 high confidence fusion transcripts across 13 tumor types. Our fusion prediction was validated by evidence of a genomic rearrangement for 78 of 79 fusions in 48 glioma samples where whole-genome sequencing data were available. Cancers with higher levels of genomic instability showed a corresponding increase in fusion transcript frequency, whereas tumor samples harboring fusions contained statistically significantly fewer driver gene mutations, suggesting an important role for tumorigenesis. We identified at least one in-frame protein kinase fusion in 324 of 4366 samples (7.4%). Potentially druggable kinase fusions involving ALK, ROS, RET, NTRK and FGFR gene families were detected in bladder carcinoma (3.3%), glioblastoma (4.4%), head and neck cancer (1.0%), low-grade glioma (1.5%), lung adenocarcinoma (1.6%), lung squamous cell carcinoma (2.3%) and thyroid carcinoma (8.7%), suggesting a potential for application of kinase inhibitors across tumor types. Inframe fusion transcripts involving histone methyltransferase or histone demethylase genes were detected in 111 samples (2.5%) and may additionally be considered as therapeutic targets. In summary, we described the landscape of transcript fusions detected across a large number of tumor samples and revealed fusion events with clinical relevance that have not been previously recognized. Our results support the concept of basket clinical trials where patients are matched with experimental therapies based on their genomic profile rather than the tissue where the tumor originated.

DOI： 10.1038/onc.2014.406

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MASSACHUSETTS MEDICAL SOC  

BACKGROUND
Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas.
METHODS
We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes.
RESULTS
Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma.
CONCLUSIONS
The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma.

DOI： 10.1056/NEJMoa1402121

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Infiltrating stromal and immune cells form the major fraction of normal cells in tumour tissue and not only perturb the tumour signal in molecular studies but also have an important role in cancer biology. Here we describe 'Estimation of STromal and Immune cells in MAlignant Tumours using Expression data' (ESTIMATE)-a method that uses gene expression signatures to infer the fraction of stromal and immune cells in tumour samples. ESTIMATE scores correlate with DNA copy number-based tumour purity across samples from 11 different tumour types, profiled on Agilent, Affymetrix platforms or based on RNA sequencing and available through The Cancer Genome Atlas. The prediction accuracy is further corroborated using 3,809 transcriptional profiles available elsewhere in the public domain. The ESTIMATE method allows consideration of tumour-associated normal cells in genomic and transcriptomic studies. An R-library is available on https://sourceforge.net/projects/estimateproject/.

DOI： 10.1038/ncomms3612

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: High-grade serous ovarian cancers are heterogeneous not only in terms of clinical outcome but also at the molecular level. Our aim was to establish a novel risk classification system based on a gene expression signature for predicting overall survival, leading to suggesting novel therapeutic strategies for high-risk patients.
Experimental Design: In this large-scale cross-platform study of six microarray data sets consisting of 1,054 ovarian cancer patients, we developed a gene expression signature for predicting overall survival by applying elastic net and 10-fold cross-validation to a Japanese data set A (n = 260) and evaluated the signature in five other data sets. Subsequently, we investigated differences in the biological characteristics between high-and low-risk ovarian cancer groups.
Results: An elastic net analysis identified a 126-gene expression signature for predicting overall survival in patients with ovarian cancer using the Japanese data set A (multivariate analysis, P = 4 x 10(-20)). We validated its predictive ability with five other data sets using multivariate analysis (Tothill's data set, P = 1 x 10(-5); Bonome's data set, P = 0.0033; Dressman's data set, P = 0.0016; TCGA data set, P = 0.0027; Japanese data set B, P = 0.021). Through gene ontology and pathway analyses, we identified a significant reduction in expression of immune-response-related genes, especially on the antigen presentation pathway, in high-risk ovarian cancer patients.
Conclusions: This risk classification based on the 126-gene expression signature is an accurate predictor of clinical outcome in patients with advanced stage high-grade serous ovarian cancer and has the potential to develop new therapeutic strategies for high-grade serous ovarian cancer patients. Clin Cancer Res; 18(5); 1374-85. (C)2012 AACR.

DOI： 10.1158/1078-0432.CCR-11-2725

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Objective This study aimed to investigate whether the amount of blood loss during delivery in patients with low-lying placenta is affected by the planned mode of delivery, internal os distance, and warning bleeding. Materials and methods We conducted a single-center retrospective study encompassing women with singleton pregnancies diagnosed with low-lying placenta between January 2012 and December 2021. Data for maternal demographic details and pregnancy outcomes were extracted from the institution's records. We analyzed blood loss during delivery according to the planned delivery mode, internal os distance (≥10 mm or within 10 mm), and the occurrence of warning bleeding. We also assessed the frequency of abnormal hemorrhage at delivery. Statistical analyses included the Mann-Whitney U test and Fisher's exact probability test, with significance set at p<0.05. Results This study included 27 pregnant women. The planned delivery mode and internal os distance showed no statistically significant impact on the amount of blood loss or frequency of abnormal hemorrhage at delivery. However, the occurrence of warning bleeding had a significant effect on both factors. Conclusion In patients diagnosed with a low-lying placenta with warning bleeding, cautious delivery management is recommended owing to the possible increased risk of abnormal hemorrhage at delivery.

DOI： 10.7759/cureus.74858

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BACKGROUND: Considerable interobserver variability exists in diagnosis of ovarian high-grade endometrioid carcinoma (HGEC) and high-grade serous carcinoma (HGSC) due to histopathological similarities. While homologous recombination deficiency (HRD) correlates with drug sensitivity in HGSC, the molecular features of HGEC are unclear. METHODS: Fresh-frozen samples from 15 ovarian HGECs and 274 ovarian HGSCs in the JGOG-TR2 cohort were submitted to targeted DNA sequencing, RNA sequencing, DNA methylation array, and SNP array. We additionally analyzed 555 ovarian HGSCs from TCGA-OV and 287 endometrial high-grade carcinomas from TCGA-UCEC. RESULTS: Unsupervised clustering using copy number signatures identified four distinct tumor groups (C1, C2, C3 and C4). C1 (n = 41) showed CCNE1 amplification and poor survival. C2 (n = 160) and C3 (n = 59) showed high BRCA1/2 alteration frequency with low and moderate ploidy, respectively. C4 (n = 22) was characterized by favorable outcome, higher HGEC proportion, no BRCA1/2 alteration or CCNE1 amplification, and low levels of HRD score, ploidy, intra-tumoral heterogeneity, cell proliferation rate, and WT1 gene expression. Notably, C4 exhibited a normal endometrium-like DNA methylation profile, thus, defined as "HGEC-type" tumors, which were also identified in TCGA-OV and TCGA-UCEC. CONCLUSIONS: Ovarian "HGEC-type" tumors present a non-HRD status, favorable prognosis, and endometrial differentiation, possibly constituting a subset of clinically diagnosed HGSCs.

DOI： 10.1038/s41416-024-02837-x

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Cancer stem cells are associated with aggressive phenotypes of malignant tumors. A prominent feature of uterine endometrial cancer is the activation of the PI3K-Akt-mTOR pathway. In this study, we present variations in sensitivities to a PI3K-Akt-mTORC1 inhibitor among in vitro endometrial cancer stem cell-enriched spheroid cells from clinical specimens. The in vitro sensitivity was consistent with the effects observed in in vivo spheroid-derived xenograft tumor models. Our findings revealed a complementary suppressive effect on endometrial cancer spheroid cell growth with the combined use of aldehyde dehydrogenase (ALDH) and PI3K-Akt inhibitors. In the PI3K-Akt-mTORC1 signaling cascade, the influence of ALDH on mTORC1 was partially channeled through retinoic acid-induced lactate dehydrogenase A (LDHA) activation. LDHA inhibition was found to reduce endometrial cancer cell growth, aligning with the effects of mTORC1 inhibition. Building upon our previous findings highlighting ALDH-driven glycolysis through GLUT1 in uterine endometrial cancer spheroid cells, curbing mTORC1 enhanced glucose transport via GLUT1 activation. Notably, elevated LDHA expression correlated with adverse clinical survival and escalated tumor grade, especially in advanced stages. Collectively, our findings emphasize the pivotal role of ALDH-LDHA-mTORC1 cascade in the proliferation of endometrial cancer. Targeting the interaction between mTORC1 and ALDH-influenced glycolysis holds promise for developing novel strategies to combat this aggressive cancer.

DOI： 10.1038/s41420-024-02204-y

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Uterine rupture can heal naturally without the need for surgical intervention. However, reports on subsequent pregnancies are limited. A 27-year-old woman, gravida 2, para 1, visited our institution at seven weeks of gestation. She had previously experienced uterine rupture with postpartum hemorrhage, which had healed naturally without surgical intervention. We thoroughly explained the perinatal complications associated with the subsequent pregnancy, particularly the risk of uterine rupture recurrence, and managed her pregnancy progress carefully. We took great care to ensure that signs of a silent rupture were not missed on imaging examinations. A planned cesarean delivery was performed at 35 weeks of gestation, resulting in an uneventful pregnancy outcome. We report the details of our management of a subsequent pregnancy in a woman who had previously experienced uterine rupture with natural healing. Our findings may serve to support healthcare providers managing similar cases.

DOI： 10.7759/cureus.70322

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AIM: To analyze temporal trends and regional variations in operative vaginal delivery (OVD) in Japan. METHODS: Using the National Database of Health Insurance Claims and Specific Health Checkups of Japan from 2014 to 2021, we identified the numbers of vacuum and forceps deliveries. We analyzed annual totals and proportions of OVDs and calculated the mean age of women undergoing these deliveries. We also predicted trends in OVD for the next 20 years and compared geographical differences in the proportions of forceps deliveries among OVDs. RESULTS: During the observation period, out of 7 368 814 total births, 8.4% were through OVD, including 7.6% by vacuum and 0.8% by forceps. Both delivery methods showed an increasing trend from 2014 to 2021: vacuum deliveries rose from 7.0% to 8.7%, and forceps deliveries increased from 0.6% to 1.0%. Notably, the proportion of forceps deliveries in OVD increased from 8.1% to 10.5%. The mean age was higher for forceps deliveries than vacuum deliveries. According to our predictions, vacuum deliveries may continue to increase, but forceps deliveries may stabilize. The proportion of forceps deliveries among OVDs ranged from 0% to 38% across Japanese prefectures. CONCLUSIONS: This study shows an increase in the use of OVD in Japan from 2014 to 2021. There are large regional differences in the choice between vacuum and forceps deliveries. These findings can help us understand the practice of OVD in Japan.

DOI： 10.1111/jog.16039

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Language：Japanese   Publisher：(一社)日本糖尿病・妊娠学会  

2010～2020年に当院で周産期管理をした母児のデータベースを構築し、妊娠糖尿病(gestational diabetes mellitus:GDM)の転帰や予後を明らかにすることを目的とした。対象妊婦4385例とし、GDM群285例、対照群4100例で比較したところ対照群で周産期合併症が多かった。そこで併存疾患をもつ妊婦を除外した2240例で再解析を行い、GDM群では対照群と比較し妊娠高血圧症候群、羊水過多、heavy for dates(HFD)が有意に多い結果となった。再解析をしたことで、GDMによる周産期合併症のリスクは、併存疾患によるものより相対的に小さいことが示唆された。(著者抄録)

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Language：Japanese   Publisher：(一社)日本糖尿病・妊娠学会  

妊娠糖尿病(gestational diabetes mellitus:GDM)合併妊婦について、妊娠中のOGTTを含む指標から産後早期糖代謝異常のリスクが予測可能か検証した。当院で出産した単胎GDM妊婦を、産後OGTTの結果により正常型群と境界型以上群に分け、GDMの診断時期別(妊娠24週未満診断:E-GDM、妊娠24週以降診断:L-GDM)に、OGTTを含む妊娠中の各種指標を比較した。産後1年程度の間にGDMの約3割に耐糖能異常を生じ、境界型の割合はGDM診断時期による違いはなかった。E-GDMではGDM診断時OGTT120分値が高い場合、L-GDMでは妊娠中体重増加量が多い場合に産後の耐糖能異常を認めやすいことが判明した。(著者抄録)

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OBJECTIVE: This study aimed to determine whether the number of resected pelvic lymph nodes (PLNs) affects the prognosis of endometrial cancer (EC) patients at post-operative risk of recurrence. METHODS: JGOG2043 was a randomized controlled trial to assess the efficacy of three chemotherapeutic regimens as adjuvant therapy in EC patients with post-operative recurrent risk. A retrospective analysis was conducted on 250 patients who underwent pelvic lymphadenectomy alone in JGOG2043. The number of resected and positive nodes and other clinicopathologic risk factors for survival were retrieved. RESULTS: There were 83 patients in the group with less than 20 PLNs removed (group A), while 167 patients had 20 or more PLNs removed (group B). There was no significant difference in patients' backgrounds between the two groups, and the rate of lymph node metastasis was not significantly different. There was a trend toward fewer pelvic recurrences in group B compared with group A (3.5% vs. 9.6%; p=0.050). Although Kaplan-Meier analysis showed no statistically significant difference in survival rates between the two groups (5-year overall survival [OS]=90.3% vs. 84.3%; p=0.199), multivariate analysis revealed that resection of 20 or more nodes is one of the independent prognostic factors (hazard ratio=0.49; 95% confidence interval=0.24-0.99; p=0.048), as well as surgical stage, high-risk histology, and advanced age for OS. CONCLUSION: Resection of 20 or more PLNs was associated with improved pelvic control and better survival outcomes in EC patients at risk of recurrence who underwent pelvic lymphadenectomy alone and were treated with adjuvant chemotherapy.

DOI： 10.3802/jgo.2025.36.e3

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OBJECTIVE: This study aimed to show the results of radical radiation therapy (RT) and concurrent chemoradiotherapy (CCRT) for vulvar cancer (VC) based on data from a Japanese nationwide survey. MATERIALS AND METHODS: We collected data from 108 institutions on cases of VC diagnosed between January 2001 and December 2010. Patients with histologically proven squamous cell carcinoma and adenocarcinoma with curative intent were selected, and 172 patients with VC were included in this study. The collected data were analyzed for overall survival (OS) using the Kaplan-Meier method. Univariate and multivariate analyses were performed to examine the prognostic factors for patients with VC. RESULTS: The median follow-up period was 16.8 (range; 3.2-154.8) months. Fifty-five patients received CCRT, and 117 patients received RT alone. The 2-year OS rates (95% confidence interval [CI]) for stages I, II, III, and IV were 77.9% (55.8-100.0), 71.9% (53.8-89.9), 55.4% (42.5-68.3), and 41.5% (27.3-55.7) respectively. Univariate analyses showed that the FIGO stage (p = 0.001), tumor diameter (p = 0.005), and lymph node (LN) status (p = 0.001) were associated with OS. The concurrent use of chemotherapy resulted in a significantly longer OS in Stage III (p = 0.013). Multivariate analysis showed that the hazard ratios (95% CI) for tumor diameter, positivity for LN metastasis, and RT alone (no concurrent chemotherapy) were 1.502 (1.116-2.021), 1.801 (1.287-2.521), and 1.936 (1.187-3.159), respectively. CONCLUSIONS: Our analysis revealed that CCRT should be recommended, especially for Stage III VC patients. Further studies are warranted to determine who benefits from CCRT, considering primary tumor size and LN status. The study was registered at the University Hospital Medical Information Network (protocol number: UMIN000017080) on April 8th, 2015.

DOI： 10.1007/s11604-024-01557-9

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.xcrm.2024.101532

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DOI： 10.1007/s10396-023-01404-w

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Lynch syndrome‐associated endometrial cancer patients often present multiple synchronous tumors and this assessment can affect treatment strategies. We present a case of a 27‐year‐old woman with tumors in the uterine corpus, cervix, and ovaries who was diagnosed with endometrial cancer and exhibited cervical invasion and ovarian metastasis. Her family history suggested Lynch syndrome, and genetic testing identified a variant of uncertain significance, MLH1 p.L582H. We conducted immunohistochemical staining, microsatellite instability analysis, and Sanger sequencing for Lynch syndrome‐associated cancers in three generations of the family and identified consistent MLH1 loss. Whole‐exome sequencing for the corpus, cervical, and ovarian tumors of the proband identified a copy‐neutral loss of heterozygosity (LOH) occurring at the MLH1 position in all tumors. This indicated that the germline variant and the copy‐neutral LOH led to biallelic loss of MLH1 and was the cause of cancer initiation. All tumors shared a portion of somatic mutations with high mutant allele frequencies, suggesting a common clonal origin. There were no mutations shared only between the cervix and ovary samples. The profiles of mutant allele frequencies shared between the corpus and cervix or ovary indicated that two different subclones originating from the corpus independently metastasized to the cervix or ovary. Additionally, all tumors presented unique mutations in endometrial cancer‐associated genes such as ARID1A and PIK3CA. In conclusion, we demonstrated clonal origin and genomic diversity in a Lynch syndrome‐associated endometrial cancer, suggesting the importance of evaluating multiple sites in Lynch syndrome patients with synchronous tumors.

DOI： 10.1002/gcc.23231

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Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Endometriosis is known to be associated with an increased risk of endometrioid and clear cell ovarian cancer. However, the association between endometriosis and endometrial cancer is controversial. Therefore, we retrospectively analyzed the medical records of women with endometrial cancer who had undergone surgery at our institution to evaluate the clinicopathological relationship between endometrial cancer and endometriosis. The study included 720 women pathologically diagnosed with endometrial cancer at our hospital between 2000 and 2020. The participants were allocated to two groups of patients with endometrial cancer: patients with endometriosis (n = 101) and patients without endometriosis (n = 619). Endometrial cancer patients with endometriosis were significantly younger (median age 54.0 vs. 58.0; p = 0.002). In addition, endometrial cancer patients with endometriosis had fewer pregnancies and deliveries (median pregnancy 1.58 vs. 1.99; p = 0.019, median delivery 1.25 vs. 1.56; p = 0.012). The percentage of patients classified as stage IA was significantly higher in those with endometrial cancer with endometriosis (68.3% vs. 56.4%; p = 0.029). In the analysis of synchronous ovarian cancer, the percentage of dual primary cancer was higher in patients with endometriosis (14.9% vs. 1.6%; p &lt; 0.001). The association of young-onset early-stage endometrial cancer with endometriosis is an important finding that cannot be ignored clinically.

DOI： 10.3390/cancers15235635

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OBJECTIVE: We aimed to quantify the incidence of recurrent uterine rupture in pregnant women. DATA SOURCES: A literature search of PubMed, Web of Science, Cochrane Central, and ClinicalTrials.gov for observational studies was performed from 2000 to 2023. METHODS OF STUDY SELECTION: Of the 7,440 articles screened, 13 studies were included in the final review. We included studies of previous uterine ruptures that were complete uterine ruptures , defined as destruction of all uterine layers, including the serosa. The primary outcome was the pooled incidence of recurrent uterine rupture. Between-study heterogeneity was assessed with the I2 value. Subgroup analyses were conducted in terms of the country development status, year of publication, and study size (single center vs national study). The secondary outcomes comprised the following: 1) mean gestational age at which recurrent rupture occurred, 2) mean gestational age at which delivery occurred without recurrent rupture, and 3) perinatal complications (blood loss, transfusion, maternal mortality, and neonatal mortality). TABULATION, INTEGRATION, AND RESULTS: A random-effects model was used to pool the incidence or mean value and the corresponding 95% CI with R software. The pooled incidence of recurrent uterine rupture was 10% (95% CI 6-17%). Developed countries had a significantly lower uterine rupture recurrence rate than less developed countries (6% vs 15%, P =.04). Year of publication and study size were not significantly associated with recurrent uterine rupture. The mean number of gestational weeks at the time of recurrent uterine rupture was 32.49 (95% CI 29.90-35.08). The mean number of gestational weeks at the time of delivery without recurrent uterine rupture was 35.77 (95% CI 34.95-36.60). The maternal mortality rate was 5% (95% CI 2-11%), and the neonatal mortality rate was 5% (95% CI 3-10%). Morbidity from hemorrhage, such as bleeding and transfusion, was not reported in any study and could not be evaluated. CONCLUSION: This systematic review estimated a 10% incidence of recurrent uterine rupture. This finding will enable appropriate risk counseling in patients with prior uterine rupture. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42023395010.

DOI： 10.1097/AOG.0000000000005418

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OBJECTIVE: To compare maternal outcomes of prenatally- and non-prenatally-diagnosed placenta accreta spectrum (PAS). DATA SOURCES: A systematic literature search was performed in PubMed, the Cochrane database, and Web of Science until 28 November 2022. STUDY ELIGIBILITY CRITERIA: Studies comparing the clinical presentation of prenatally- and non-prenatally-diagnosed PAS were included. Primary outcomes were emergent cesarean delivery, hysterectomy, blood loss volume, number of transfused blood product units, urological injury, coagulopathy, reoperation, intensive care unit admission, and maternal death. We also calculated the pooled mean values for blood loss volume and the number of transfused blood product units. Secondary outcomes comprised maternal age, gestational age at birth, nulliparity, prior cesarean delivery, prior uterine procedure, assisted reproductive technology, placenta increta/percreta, and placenta previa. STUDY APPRAISAL AND SYNTHESIS METHODS: Study screening was conducted after duplicates were identified and removed. The quality of each study and the publication bias were assessed. Forest plots and I2 statistics were calculated for each study outcome for each group. The main analysis was a random-effects analysis. RESULTS: 415 abstracts and 157 full-text studies were evaluated. Thirty-one studies were analyzed. Prenatally-diagnosed PAS was associated with a significantly lower rate of emergency cesarean delivery (odds ratio (OR), 0.37; 95% CI, 0.21-0.67), higher hysterectomy rate (OR, 1.98; 95% CI, 1.02-3.83), lower blood loss volume (mean difference, -0.65; 95% CI, -1.17 to -0.13), and lower number of transfused red blood cell units (mean difference, -1.96; 95% CI, -3.25 to -0.68) compared with non-prenatally-diagnosed PAS. Pooled mean values for blood loss volume and the number of transfused blood product units tended to be lower in the prenatally- vs non-prenatally-diagnosed PAS groups. Nulliparity (OR, 0.14; 95% CI, 0.10-0.20), prior cesarean delivery (OR, 6.81; 95% CI, 4.12-11.25), assisted reproductive technology (OR, 0.19; 95% CI, 0.06-0.61), placenta increta/percreta (OR, 3.97; 95% CI, 2.24- 7.03), and placenta previa (OR, 6.81; 95% CI, 4.12-11.25) showed statistical significance. No significance differences were found for the other outcomes. CONCLUSIONS: Despite its severity, the positive impact of prenatally-diagnosed PAS on outcomes underscores the necessity of a prenatal diagnosis. Additionally, the pooled mean values provide a preoperative preparation guideline.

DOI： 10.1016/j.ajogmf.2023.101197

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BRCA1/2 mutations are robust biomarkers for platinum-based chemotherapy in epithelial ovarian cancers. However, BRCA1/2 mutations in clear cell ovarian carcinoma (CCC) are less frequent compared to high-grade serous ovarian cancer (HGSC). The discovery of biomarkers that can be applied to CCC is an unmet need in chemotherapy. Schlafen 11 (SLFN11) has attracted attention as a novel sensitizer for DNA-damaging agents including platinum. In this study, we investigated the utility of SLFN11 in HGSC and CCC for platinum-based chemotherapy. SLFN11 expression was analyzed retrospectively by immunohistochemistry across 326 ovarian cancer samples. The clinicopathologic significance of SLFN11 expression was analyzed across 57 advanced HGSC as a discovery set, 96 advanced HGSC as a validation set, and 57 advanced CCC cases, all of whom received platinum-based chemotherapy. BRCA1/2 mutation was analyzed using targeted-gene sequencing. In the HGSC cohort, the SLFN11-positive and BRCA mutation group showed significantly longer while the SLFN11-negative and BRCA wild-type group showed significantly shorter progression-free survival and overall survival. Moreover, SLFN11-positive HGSC shrunk significantly better than SLFN11-negative HGSC after neoadjuvant chemotherapy. Comparable results were obtained with CCC but without consideration of BRCA1/2 mutation due to a small population. Multivariate analysis identified SLFN11 as an independent factor for better survival in HGSC and CCC. The SLFN11-dependent sensitivity to platinum and PARP inhibitors were validated with genetically modified non-HGSC ovarian cancer cell lines. Our study reveals that SLFN11 predicts platinum sensitivity in HGSC and CCC independently of BRCA1/2 mutation status, indicating that SLFN11 assessment can guide treatment selection in HGSC and CCC.

DOI： 10.1158/1535-7163.MCT-23-0257

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Language：Japanese   Publisher：新潟産科婦人科学会  

インドシアニングリーン(ICG;Indocyanine green)は,(1)肝機能検査,(2)循環機能検査,血管及び組織の血流評価,(4)センチネルリンパ節の同定,という4項目で保険適応を得ている試薬である。近赤外光に対し蛍光発光する特徴を持っており,対応の腹腔鏡システムであれば,手元のスイッチ操作で容易に赤外光観察モードに変更してその蛍光発光を観察することができる。付属の溶解液に溶解して経静脈内投与すると,投与後30秒から1分程度で蛍光の観察が可能となり,半減期も3-4分と短いことから反復投与も可能である。また,ヨードアレルギー患者には禁忌であるが,大きな有害事象の報告もなく,汎用性・安全性の高い試薬とされている。今回,卵巣温存予定の腹腔鏡下子宮全摘術の際に,左骨盤漏斗靱帯の一部損傷と左卵巣の血流不全を疑う場面が生じた。肉眼的には卵巣は正常色調であったが,ICGの保険適応の1つである「(3)血管及び組織の血流評価」に基づいてICGによる左卵巣の血流評価を行ったところ,周囲臓器が明瞭に蛍光発光する中で左卵巣のみ発光が認められなかったため,血流途絶あるいは極度の血流低下と判断し,左卵巣を摘出した。ICGの投与により,比較的簡便に,客観的な血流評価並びに卵巣温存の可否が判断可能であった症例を経験したため報告する。(著者抄録)

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IMPORTANCE: Randomized clinical trials examining the effectiveness of neoadjuvant chemotherapy (NACT) for advanced ovarian cancer predominantly included patients with high-grade serous carcinomas. The use and outcomes of NACT in less common epithelial carcinomas are understudied. OBJECTIVE: To investigate the uptake and survival outcomes in treatment with NACT for less common histologic subtypes of epithelial ovarian cancer. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study and systematic literature review with meta-analysis was conducted using the National Cancer Database from 2006 to 2017 and the National Cancer Institute's Surveillance, Epidemiology, and End Results Program from 2006 to 2019. Data analysis was performed from July 2022 to April 2023. The evaluation included patients with stage III to IV ovarian cancer with clear cell, mucinous, or low-grade serous histologic subtypes who received multimodal treatment with surgery and chemotherapy. EXPOSURES: Exposure assignment per the sequence of treatment: primary debulking surgery (PDS) followed by chemotherapy (PDS group) or NACT followed by interval surgery (NACT group). MAIN OUTCOMES AND MEASURES: Temporal trends and characteristics of NACT use were assessed using multivariable analysis, and overall survival (OS) was assessed with the inverse probability of treatment weighting propensity score. RESULTS: A total of 3880 patients were examined in the National Cancer Database including 1829 women (median age, 56 [IQR, 49-63] years) with clear cell, 1156 women (median age, 53 [IQR, 42-64] years) with low-grade serous, and 895 women (median age, 57 [IQR, 48-66] years) with mucinous carcinomas. NACT use increased in patients with clear cell (from 10.2% to 16.2%, 58.8% relative increase; P < .001 for trend) or low-grade serous (from 7.7% to 14.2%, 84.4% relative increase; P = .007 for trend) carcinoma during the study period. This association remained consistent in multivariable analysis. NACT use also increased, but nonsignificantly, in mucinous carcinomas (from 8.6% to 13.9%, 61.6% relative increase; P = .07 for trend). Across the 3 histologic subtypes, older age and stage IV disease were independently associated with NACT use. In a propensity score-weighted model, the NACT and PDS groups had comparable OS for clear cell (4-year rates, 31.4% vs 37.7%; hazard ratio [HR], 1.12; 95% CI, 0.95-1.33) and mucinous (27.0% vs 26.7%; HR, 0.90; 95% CI, 0.68-1.19) carcinomas. For patients with low-grade serous carcinoma, NACT was associated with decreased OS compared with PDS (4-year rates, 56.4% vs 81.0%; HR, 2.12; 95% CI, 1.55-2.90). Increasing NACT use and histologic subtype-specific survival association were also found in the Surveillance, Epidemiology, and End Results Program cohort (n = 1447). A meta-analysis of 4 studies, including the current study, observed similar OS associations for clear cell (HR, 1.13; 95% CI, 0.96-1.34; 2 studies), mucinous (HR, 0.93; 95% CI, 0.71-1.21; 2 studies), and low-grade serous (HR, 2.11; 95% CI, 1.63-2.74; 3 studies) carcinomas. CONCLUSIONS AND RELEVANCE: Despite the lack of data on outcomes of NACT among patients with less common carcinomas, this study noted that NACT use for advanced disease has gradually increased in the US. Primary chemotherapy for advanced-stage, low-grade serous ovarian cancer may be associated with worse survival compared with PDS.

DOI： 10.1001/jamanetworkopen.2023.18602

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OBJECTIVE: We aimed to conduct a systematic review and meta-analysis to assess clinical characteristics related to pathologically proven placenta accreta spectrum (PAS) without placenta previa. DATA SOURCES: A literature search of PubMed, the Cochrane database, and Web of Science was performed from inception to September 7, 2022. STUDY ELIGIBILITY CRITERIA: The primary outcomes were invasive placenta (including increta or percreta), blood loss, hysterectomy, and antenatal diagnosis. Additionally, maternal age, assisted reproductive technology, previous cesarean section, and previous uterine procedures were investigated as potential risk factors. The inclusion criteria were studies evaluating the clinical presentation of pathologically diagnosed PAS without placenta previa. STUDY APPRAISAL AND SYNTHESIS METHODS: Study screening was conducted after duplicates were identified and removed. The quality of each study and the publication bias were assessed. Forest plots and I2 statistics were calculated for each study outcome for each group. The main analysis was a random-effects analysis. RESULTS: Among 2598 studies that were initially retrieved, five were included in the review. With the exception of one study, four studies could be included in the meta-analysis. This meta-analysis showed that PAS without placenta previa was associated with a less risk of invasive placenta (OR, 0.24; 95% CI, 0.16-0.37), blood loss (MD, -1.19; 95% CI, -2.09 to -0.28) and hysterectomy (OR, 0.11; 95% CI, 0.02-0.53), and more difficult to diagnose prenatally (OR, 0.13; 95% CI, 0.04-0.45) than PAS with placenta previa. Additionally, assisted reproductive technology and a previous uterine procedure were strong risk factors for PAS without placenta previa, while previous cesarean section was a strong risk factor for PAS with placenta previa. CONCLUSIONS: The differences in clinical aspects of PAS with and without placenta previa need to be understood.

DOI： 10.1016/j.ajogmf.2023.101027

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The development of new treatments for gynecological malignancies has been conducted mainly through collaborative international phase III trials led by the United States and Europe. The survival outcomes of many gynecological malignancies have greatly improved as a result. Recent large-scale genome-wide association studies have revealed that drug efficacy and adverse event profiles are not always uniform. Thus, it is important to validate new treatment options in each country to safely and efficiently provide newly developed treatment options to patients with gynecological malignancies. The Japanese Gynecologic Oncology Group (JGOG) is conducting 5 cohort studies (JGOG 3026, 3027, 3028, 3030, and 3031) to establish real-world data (RWD) of poly(ADP-ribose) polymerase (PARP) inhibitor use in patients with advanced or recurrent epithelial ovarian cancer. The RWD constructed will be used to provide newly developed PARP inhibitors for women with advanced or recurrent ovarian cancer in a safer and more efficient manner as well as to develop further treatment options. In 2022, The JGOG, Korean Gynecologic Oncology Group, Chinese Gynecologic Cancer Society, and Taiwanese Gynecologic Oncology Group established the East Asian Gynecologic Oncology Trial Group to collaborate with East Asian countries in clinical research on gynecologic malignancies and disseminate new knowledge on gynecologic malignancies from Asia. The JGOG will conduct a collaborative integrated analysis of the RWD generated from Asian countries and disseminate real-world clinical knowledge regarding new treatment options that have been clinically implemented.

DOI： 10.3802/jgo.2023.34.e62

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Although the gross and microscopic features of squamous cell carcinoma arising from ovarian mature cystic teratoma (MCT-SCC) vary from case to case, the spatial spreading of genomic alterations within the tumor remains unclear. To clarify the spatial genomic diversity in MCT-SCCs, we performed whole-exome sequencing by collecting 16 samples from histologically different parts of two MCT-SCCs. Both cases showed histological diversity within the tumors (case 1: nonkeratinizing and keratinizing SCC and case 2: nonkeratinizing SCC and anaplastic carcinoma) and had different somatic mutation profiles by histological findings. Mutation signature analysis revealed a significantly enriched apolipoprotein B mRNA editing enzyme catalytic subunit (APOBEC) signature at all sites. Intriguingly, the spread of genomic alterations within the tumor and the clonal evolution patterns from nonmalignant epithelium to cancer sites differed between cases. TP53 mutation and copy number alterations were widespread at all sites, including the nonmalignant epithelium, in case 1. Keratinizing and nonkeratinizing SCCs were differentiated by the occurrence of unique somatic mutations from a common ancestral clone. In contrast, the nonmalignant epithelium showed almost no somatic mutations in case 2. TP53 mutation and the copy number alteration similarities were observed only in nonkeratinizing SCC samples. Nonkeratinizing SCC and anaplastic carcinoma shared almost no somatic mutations, suggesting that each locally and independently arose in the MCT. We demonstrated that two MCT-SCCs with different histologic findings were highly heterogeneous tumors with clearly different clones associated with APOBEC-mediated mutagenesis, suggesting the importance of evaluating intratumor histological and genetic heterogeneity among multiple sites of MCT-SCC.

DOI： 10.1111/cas.15754

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AIM: In this review, We compared clinical characteristics of pregnant women aged 50 and older with those aged 45-49. Pregnant women ≥45 years are strongly associated with pregnancy-related complications, such as cesarean section rate, gestational hypertension, gestational diabetes mellitus, and preterm birth. Although pregnant women ≥50 years are considered more high-risk, differences in pregnancy outcomes between those over 45 and 50 years of age are unclear. METHODS: Our source strategy included using PubMed, the Cochrane Central Register of Controlled Trials, and Web of Science databases to include studies published between January 1, 2010 and September 30, 2022. The study population was pregnant women 50 years and older; the control group was pregnant women aged 45-49 years. Primary outcomes were cesarean section, gestational hypertension, gestational diabetes mellitus, and preterm birth. The secondary outcomes were small-for-gestational age, 5-min Apgar score < 7, neonatal intensive care unit admission (as neonatal outcomes), nulliparity, assisted reproductive technology (ART), and multifetal pregnancy (as maternal backgrounds). RESULTS: The incidence of cesarean section, gestational hypertension, and preterm delivery was significantly higher in those 50 years and older; however, significant differences disappeared when pooled analyses were limited to singleton pregnancies. ART was significantly more likely to be used for conception of pregnant women ≥50 years. Infants of women ≥50 years were more likely to be admitted to NICUs. CONCLUSIONS: The differences in outcomes between the two groups are obviously influenced by multiple pregnancies, therefore, reproductive medicine specialists should aim for singleton pregnancies in ART.

DOI： 10.1111/jog.15662

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

卵黄嚢腫瘍(YST)は稀に閉経後にも発生し,多くは上皮性腫瘍と混在し,組織学的に類似した明細胞癌との鑑別も重要となる.今回,組織学的診断に苦慮した症例を経験したため報告する.症例は67歳,突然の腹痛を伴う15cm大の多房性卵巣腫瘍で一部に充実部分を認め,血性腹水の出現とAFP,CA125,CA19-9の上昇を伴うことから,卵巣悪性腫瘍の破裂と診断して,緊急手術を行った.IC2期のYSTと診断し,速やかにBEP療法を開始し,1サイクル終了時にはAFPが陰性化した.閉経後のYSTであり,上皮性腫瘍由来の可能性を考慮して再検討を行った.腫瘍の主体となる粘液性腫瘍にはCDX2,p53が陽性で腸型粘液産生を認め,YSTを認めた充実部分では,AFP,SALL4,CDX2,p53が陽性でCK7,EMA,ARID1Aが陰性という所見であり,体細胞を起源として発生したYSTと診断した.BEP療法による重篤な骨髄抑制が出現し,2サイクル目以降はレジメンをTC療法に変更して治療を行い,術後17カ月時点において無再発で経過中である.近年,閉経後YSTは体細胞腫瘍が発生由来とされており,本症例も免疫組織化学の結果からsomatic YSTであることが推察された.閉経後のYSTでは,上皮性腫瘍との関連性を考慮した診断ならびに治療法選択が必要である.(著者抄録)

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Language：Japanese   Publisher：新潟産科婦人科学会  

胎児骨系統疾患は新生児期早期に管理を要する疾患であるが,超音波検査での胎児診断の精度は高くはない。今回,Three-dimensional computed tomography(以下,3D-CT)が胎児診断に有用であった胎児骨系統疾患の3例を経験したため報告する。症例1は妊娠16週より胎児骨系統疾患が疑われ,超音波検査で極めて予後不良な疾患が想定されたが,妊娠継続を希望され胎児3D-CTを撮像した。画像所見から骨形成不全症II型を強く疑い,分娩時損傷を回避するために帝王切開で出生した。症例2,3は妊娠27週頃より顕著な四肢の短縮を認め,胎児3D-CTによりそれぞれ骨形成不全症,軟骨無形成症と胎児診断した。3症例とも出生後速やかに新生児集中治療室(Neonatal Intensive Care Unit;NICU)に入室し,呼吸管理や画像検査,遺伝子検索などの早期介入につながった。胎児3D-CTは鑑別診断や重症度の診断精度が上がり,予後や治療方針を両親に事前に情報提供でき,かつ周産期管理指針が明確になる点で有用な検査であると考えられた。(著者抄録)

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TCGA network has clarified that approximately 50% of high-grade serous ovarian cancers show homologous recombination deficiency (HRD). However, the frequency of HRD in Japanese patients with ovarian cancer remains unclear. We aimed to identify the frequency of HR-associated gene mutations in Japanese patients with ovarian cancer. The JGOG3025 study is a multicenter collaborative prospective observational study involving 65 study sites throughout Japan. We recruited 996 patients who were clinically diagnosed with ovarian cancer before surgery from March 2017 to March 2019, and 701 patients were eligible according to the criteria. We used frozen tumor tissues to extract DNA and performed next generation sequencing for 51 targeted genes (including 29 HR-associated genes) in 701 ovarian cancers (298 high-grade serous cases, 189 clear cell cases, 135 endometrioid cases, 12 mucinous cases, 3 low-grade serous cases, and 64 others). HRD was defined as positive when at least one HR-associated gene was mutated. The frequencies of HRD and tumor BRCA1/2 mutations were 45.2% (317/701) and 18.5% (130/701), respectively, in the full analysis set. Next, we performed multivariate Cox proportional hazards regression analysis for progression-free survival (PFS) and overall survival (OS). Advanced-stage ovarian cancer patients with HRD had adjusted hazard ratios of 0.72 (95% CI, 0.55-0.94) and 0.57 (95% CI, 0.38-0.86) for PFS and OS, respectively, compared to those without HRD (p = 0.016 and 0.007). Our study demonstrated that mutations in HR-associated genes were associated with prognosis. Further studies are needed to investigate the prognostic impact of each HR-associated gene in ovarian cancer.

DOI： 10.1111/cas.15747

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/s41416-022-02122-9

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Other Link： https://www.nature.com/articles/s41416-022-02122-9

Publishing type：Research paper (scientific journal)   Publisher：AME Publishing Company  

DOI： 10.21037/atm-23-352

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Language：Japanese   Publisher：東北連合産科婦人科学会・北日本産科婦人科学会  

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Language：Japanese   Publisher：東北連合産科婦人科学会・北日本産科婦人科学会  

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Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publisher：金原出版(株)  

＜文献概要＞肝疾患を有するがん患者の場合,その肝機能によっては化学療法における抗がん薬の用量調整を必要とするが,一方で抗がん薬の減量や休薬はがんの進行・増悪のリスクをはらんでいる。また,抗がん薬の多くは肝臓で代謝されるため,治療中に薬剤性肝障害を引き起こす可能性があり,慎重な管理が求められる。特に,B型肝炎ウイルスキャリアや既感染患者では化学療法によってB型肝炎ウイルス再活性化を引き起こす可能性もあり,ガイドラインに沿って対応すべきであろう。肝臓疾患を有する婦人科がん患者の治療にあたっては,肝臓専門医との協力により,治療によるベネフィットとリスクを把握して,症例ごとの慎重な対応が重要となる。

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Large-scale data on maternal and neonatal outcomes of pregnancy-associated cervical cancer in Japan are scarce, and treatment strategies have not been established. This multicenter retrospective observational study investigated clinical features and trends in pregnancy-associated cervical cancer treatments at 523 hospitals in Japan. We included cervical cancer cases that were histologically diagnosed (between 1 January 2012, and 31 December 2017), and their clinical information was retrospectively collected. Of 40 patients diagnosed with pregnancy-associated cervical cancer at ≥22 gestational weeks, 34 (85.0%) were carefully followed until delivery without intervention. Of 163 diagnosed at &lt;22 gestational weeks, 111 continued and 52 terminated their pregnancy. Ninety patients with stage IB1 disease had various treatment options, including termination of pregnancy. The 59 stage IB1 patients who continued their pregnancy were categorized by the primary treatment into strict follow-up, conization, trachelectomy, and neoadjuvant chemotherapy groups, with no significant differences in progression-free or overall survival. The birth weight percentile at delivery was smaller in the neoadjuvant chemotherapy group than in the strict follow-up group (p = 0.029). Full-term delivery rate was relatively higher in the trachelectomy group (35%) than in the other groups. Treatment decisions for pregnancy-associated cervical cancer are needed after estimating the stage, considering both maternal and fetal benefits.

DOI： 10.3390/cancers14133072

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Sentinel node navigation surgery (SNNS) is used in clinical practice for the treatment of cervical cancer. This study aimed to elucidate the appropriate sentinel lymph node (SLN) mapping method and assess the safety and benefits of SNNS. We searched the PubMed, Ichushi, and Cochrane Library databases for randomized controlled trials (RCT) and studies on SLN in cervical cancer from January 2012 to December 2020. Two authors independently assessed study quality and extracted data. We quantitatively analyzed the detection rate, sensitivity/specificity, and complications and reviewed information, including the survival data of SLN biopsy (SLNB) without pelvic lymphadenectomy (PLND). The detection rate of SLN mapping in the unilateral pelvis was median 95.7% and 100% and in the bilateral pelvis was median 80.4% and 90% for technetium-99 m (Tc) with/without blue dye (Tc w/wo BD) and indocyanine green (ICG) alone, respectively. The sensitivity and specificity of each tracer were high; the area under the curve of each tracer was 0.988 (Tc w/wo BD), 0.931 (BD w/wo Tc), 0.966 (ICG), and 0.977 (carbon nanoparticle). Morbidities including lymphedema, neurological symptoms and blood loss were associated with PLND. One RCT and five studies all showed SNNS without systematic PLND does not impair recurrence or survival in early-stage cervical cancer with a tumor size ≤ 2-4 cm. Both Tc w/wo BD and ICG are appropriate SLN tracers. SNNS can reduce the morbidities associated with PLND without affecting disease progression in early-stage cervical cancer.

DOI： 10.1007/s10147-022-02178-w

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BACKGROUND: Poly (adenosine diphosphate)-ribose polymerase (PARP) inhibitors for tumors with homologous recombination deficiency (HRD), including pathogenic mutations in BRCA1/2, have been developed. Genomic analysis revealed that about 20% of uterine leiomyosarcoma (uLMS) have HRD, including 7.5%-10% of BRCA1/2 alterations and 4%-6% of carcinomas of the uterine corpus, and 2.5%-4% of the uterine cervix have alterations of BRCA1/2. Preclinical and clinical case reports suggest that PARP inhibitors may be effective against those targets. The Japanese Gynecologic Oncology Group (JGOG) is now planning to conduct a new investigator-initiated clinical trial, JGOG2052. METHODS: JGOG2052 is a single-arm, open-label, multi-center, phase 2 clinical trial to evaluate the efficacy and safety of niraparib monotherapy for a recurrent or persistent rare fraction of gynecologic malignancies with BRCA1/2 mutations except for ovarian cancers. We will independently consider the effect of niraparib for uLMS or other gynecologic malignancies with BRCA1/2 mutations (cohort A, C) and HRD positive uLMS without BRCA1/2 mutations (cohort B). Participants must have 1-3 lines of previous chemotherapy and at least one measurable lesion according to RECIST (v.1.1). Niraparib will be orally administered once a day until lesion exacerbation or unacceptable adverse events occur. Efficacy will be evaluated by imaging through an additional computed tomography scan every 8 weeks. Safety will be measured weekly in cycle 1 and every 4 weeks after cycle 2 by blood tests and physical examinations. The sample size is 16-20 in each of cohort A and B, and 31 in cohort C. Primary endpoint is the objective response rate. TRIAL REGISTRATION: Japan Primary Registries Network (JPRN) Identifier: jRCT2031210264.

DOI： 10.3802/jgo.2022.33.e55

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Ovarian clear cell carcinoma (OCCC) is associated with chemotherapy resistance and poor prognosis, especially in advanced cases. Although comprehensive genomic analyses have clarified the significance of genomic alterations such as ARID1A and PIK3CA mutations in OCCC, therapeutic strategies based on genomic alterations have not been confirmed. On the other hand, OCCC is clinically characterized by a high incidence of thromboembolism. Moreover, OCCC specifically shows high expression of tissue factor and interleukin-6, which play a critical role in cancer-associated hypercoagulation and may be induced by OCCC-specific genetic alterations or the endometriosis-related tumor microenvironment. In this review, we focused on the association between cancer-associated hypercoagulation and molecular biology in OCCC. Moreover, we reviewed the effectiveness of candidate drugs targeting hypercoagulation, such as tissue factor- or interleukin-6-targeting drugs, anti-inflammatory drugs, anti-hypoxia signaling drugs, anticoagulants, and combined immunotherapy with these drugs for OCCC. This review is expected to contribute to novel basic research and clinical trials for the prevention, early detection, and treatment of OCCC focused on hypercoagulation.

DOI： 10.3390/cancers14092125

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMC  

Background Our previous study demonstrated the safety and effectiveness of abdominal radical trachelectomy during pregnancy but did not focus on the fetus. This study aimed to clarify the influence of abdominal radical trachelectomy performed during pregnancy on the fetus. Methods Eight cervical cancer patients who underwent abdominal radical trachelectomy at our hospital between February 2013 and August 2020 were enrolled in this study. To assess the peri- and postoperative influence on the fetus, we performed fetal heart monitoring at 30-min intervals during abdominal radical trachelectomy and calculated the estimated fetal body weight and resistance indexes of the middle cerebral artery and umbilical artery from postsurgery until delivery. Results Four out of eight patients had preterm birth due to chorioamnionitis in one case and consideration of the recurrent risk of cervical cancer in three cases. Fetal heart monitoring during abdominal radical trachelectomy revealed deceleration just once in one case but no abnormal findings in the other cases. In all cases, the fetal growth after abdominal radical trachelectomy was normal until delivery. No abnormal Doppler findings were detected in the middle cerebral artery or umbilical artery. Conclusion Our findings clarified that abdominal radical trachelectomy performed for the treatment of early-stage cervical cancer during pregnancy has no obvious influence on fetal growth. Next, it is necessary to evaluate the growth and development of children delivered from mothers who have undergone abdominal radical trachelectomy during pregnancy.

DOI： 10.1186/s12884-022-04671-6

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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It has become evident that somatic mutations in cancer-associated genes accumulate in the normal endometrium, but spatiotemporal understanding of the evolution and expansion of mutant clones is limited. To elucidate the timing and mechanism of the clonal expansion of somatic mutations in cancer-associated genes in the normal endometrium, we sequence 1311 endometrial glands from 37 women. By collecting endometrial glands from different parts of the endometrium, we show that multiple glands with the same somatic mutations occupy substantial areas of the endometrium. We demonstrate that "rhizome structures", in which the basal glands run horizontally along the muscular layer and multiple vertical glands rise from the basal gland, originate from the same ancestral clone. Moreover, mutant clones detected in the vertical glands diversify by acquiring additional mutations. These results suggest that clonal expansions through the rhizome structures are involved in the mechanism by which mutant clones extend their territories. Furthermore, we show clonal expansions and copy neutral loss-of-heterozygosity events occur early in life, suggesting such events can be tolerated many years in the normal endometrium. Our results of the evolutionary dynamics of mutant clones in the human endometrium will lead to a better understanding of the mechanisms of endometrial regeneration during the menstrual cycle and the development of therapies for the prevention and treatment of endometrium-related diseases.

DOI： 10.1038/s41467-022-28568-2

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Neuroendocrine neoplasms of the colon and rectum are colorectal epithelial neoplasms with neuroendocrine differentiation. A platinum regimen used for small cell lung cancer is the currently recommended chemotherapy for gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs), regardless of the organ. The BRAF V600E mutation has been recently reported as a druggable driver mutation in colorectal NECs. In BRAF V600E mutant colorectal cancer, a combination of BRAF inhibitor and anti-epidermal growth factor receptor (EGFR) antibody, with or without a MEK inhibitor, is recommended. Here, we report the case of 77-year-old man who had lymph node recurrence after surgery for primary ascending colonic NEC. Two cytotoxic regimens, cisplatin plus irinotecan and modified FOLFOX6, were administered as first- and second-line chemotherapies with no remarkable response observed. At this point, genetic analysis confirmed the tumor harbored a BRAF V600E mutation. Thus, a regimen of BRAF inhibitor plus anti-EGFR antibody was administered. After commencing this regimen, carcinoembryonic antigen levels decreased within normal range, and there was dramatic shrinkage of the lymph node metastases observed by chest and abdominal computed tomography scans. To our knowledge, this is the first reported case of a colorectal NEC responding to a BRAF inhibitor and anti-EGFR antibody.

DOI： 10.1007/s12328-022-01599-4

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/s10038-021-01003-y

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Other Link： https://www.nature.com/articles/s10038-021-01003-y

Language：Japanese   Publisher：新潟産科婦人科学会  

当院でBevacizumab(Bev)を導入した進行・再発卵巣癌・卵管癌・腹膜癌125例を対象に有害事象について検討を行った。その結果、Grade3以上の有害事象として高血圧16例(12.8%)、蛋白尿5例(4.0%)、血栓塞栓症3例(2.4%)、消化管穿孔2例(1.6%)が認められた。消化管穿孔例はともにGrade4で緊急手術を要し、それぞれ腫瘍と直腸癒着・浸潤部分の穿孔、高度癒着部分の穿孔であった。

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Language：Japanese   Publisher：新潟産科婦人科学会  

当院でBevacizumab(Bev)を導入した進行・再発卵巣癌・卵管癌・腹膜癌125例を対象に有害事象について検討を行った。その結果、Grade3以上の有害事象として高血圧16例(12.8%)、蛋白尿5例(4.0%)、血栓塞栓症3例(2.4%)、消化管穿孔2例(1.6%)が認められた。消化管穿孔例はともにGrade4で緊急手術を要し、それぞれ腫瘍と直腸癒着・浸潤部分の穿孔、高度癒着部分の穿孔であった。

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Uterine leiomyosarcoma (ULMS) is a malignancy, which arises from the uterine smooth muscle. Because of its rarity, aggressive nature, and extremely poor prognosis, the molecular mechanisms driving ULMS remain elusive. To identify candidate cancer genes (CCG) driving ULMS, we conducted an in vivo Sleeping Beauty (SB) transposon mutagenesis screen in uterine myometrium-specific, PTEN knockout, KRAS mutant (PTEN KO/KRAS) mice. ULMS quickly developed in SB PTEN KO/KRAS mice, but not in PTEN KO/KRAS mice, demonstrating the critical importance of SB mutagenesis for driving ULMS in this model. Subsequent sequencing of SB insertion sites in these tumors identified 19 ULMS CCGs that were significantly enriched in known cancer genes. Among them, Zfp217 and Sfmbt2 functioned at early stages of tumor initiation and appeared to be oncogenes. Expression of ZNF217, the human homolog of ZFP217, was shown to be elevated in human ULMS compared with paired normal uterine smooth muscle, where it negatively correlated with patient prognosis. Inhibition of ZNF217 suppressed, whereas overexpression induced, proliferation, survival, migration, and stemness of human ULMS. In a second ex vivo ULMS SB metastasis screen, three CCGs were identified that may drive ULMS metastasis to the lung. One of these CCGs, Nrd1 (NRDC in humans), showed stronger expression in human metastatic tumors compared with primary ULMS and negatively associated with patient survival. NRDC knockdown impaired migration and adhesion without affecting cell proliferation, whereas overexpression had the opposite effect. Together, these results reveal novel mechanism driving ULMS tumorigenesis and metastasis and identify ZNF217 and NRDC as potential targets for ULMS therapy. SIGNIFICANCE: An in vivo Sleeping Beauty transposon mutagenesis screen identifies candidate cancer genes that drive initiation and progression of uterine leiomyosarcoma and may serve as therapeutic targets.

DOI： 10.1158/0008-5472.CAN-21-0356

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Patient-derived cells and xenografts retain the biological characteristics of clinical cancers and are instrumental in gaining a better understanding of the chemoresistance of cancer cells. Here, we have established a panel of patient-derived spheroids from clinical materials of ovarian cancer. Systematic evaluation using therapeutic agents indicated that sensitivity to platinum-based compounds significantly varied among the spheroids. To understand the molecular basis of drug sensitivity, we performed integrative analyses combining chemoresistance data and gene expression profiling of the ovarian cancer patient-derived spheroids. Correlation analyses revealed that cisplatin resistance was significantly associated with elevated levels of glucose-6-phosphate dehydrogenase (G6PD) and glutathione-producing redox enzymes. Accordingly, cisplatin-resistant spheroids established in vitro showed elevated levels of G6PD and active glutathione. Moreover, treatment with a G6PD inhibitor in combination with cisplatin suppressed spheroid proliferation in vitro and largely eradicated peritoneal metastasis in mouse xenograft models. Furthermore, G6PD expression was elevated during carcinogenesis and associated with poor prognosis. Thus, the combination of gene expression data and chemosensitivity revealed the essential roles of G6PD-driven redox metabolism in cisplatin resistance, underscoring the significance of an integrative approach using patient-derived cells.

DOI： 10.1016/j.canlet.2021.08.018

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The histology of the endometrium has traditionally been established by observation of two-dimensional (2D) pathological sections. However, because human endometrial glands exhibit coiling and branching morphology, it is extremely difficult to obtain an entire image of the glands by 2D observation. In recent years, the development of three-dimensional (3D) reconstruction of serial pathological sections by computer and whole-mount imaging technology using tissue clearing methods with high-resolution fluorescence microscopy has enabled us to observe the 3D histoarchitecture of tissues. As a result, 3D imaging has revealed that human endometrial glands form a plexus network in the basalis, similar to the rhizome of grass, whereas mouse uterine glands are single branched tubular glands. This review summarizes the relevant literature on the 3D structure of mouse and human endometrium and discusses the significance of the rhizome structure in the human endometrium and the expected role of understanding the 3D tissue structure in future applications to systems biology.

DOI： 10.3390/jpm11080713

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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BACKGROUND: Malignancy during pregnancy is increasing, and the most common type of malignancy is uterine cervical cancer. When planning the treatment of cervical cancer, it is important to look for signs of metastasis before surgery, especially metastasis to the lymph nodes. In this report, we assessed the diagnostic value of positron emission tomography/magnetic resonance imaging (PET/MRI) for evaluating cervical cancer propagation before surgery, with a focus on pregnant women. CASE PRESENTATION: 18F Fluorodeoxyglucose (FDG)-PET/MRI was performed in seven pregnant cervical cancer patients (28-34 years old) at 9-18 gestational weeks. In case #5, a second PET/MRI was performed at 24 gestational weeks. Of seven FDG-PET/MRI examination series in six cases (cases #1-6), FDG-PET/MR imaging could detect cervical tumors with abnormal FDG accumulation; these tumors were confirmed with a standardized uptake value max (SUV max) titer of 4.5-16. A second PET/MRI examination in case #5 revealed the same SUV max titer as the first examination. In these six imaging series (cases #1-5), there were no signs of cancer metastasis to the parametrium and lymph nodes. However, in case #6, abnormal FDG accumulation in the left parametrial lymph nodes was also detectable. Pathological examination showed lymph node metastasis in case #6. In case #7, PET/MRI could not detect any abnormal FDG accumulation in the cervix and other sites. Cone biopsy demonstrated only micro-invasive squamous cell carcinoma. After treatment for cervical cancer, all seven patients have had no recurrence of disease within the follow-up period (2.8-5.6 years), and their children have developed appropriately. CONCLUSION: PET/MRI is an effective imaging tool to evaluate cervical cancer progression in pregnancy.

DOI： 10.1186/s12884-021-03766-w

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BACKGROUND: Mesenteric lymph node (MLN) involvement is often observed in ovarian cancer (OC) with rectosigmoid invasion. This study aimed to investigate the clinical significance of MLN involvement in the pattern of liver metastasis in patients with OC. METHODS: We included 85 stage II-IV OC patients who underwent primary or interval debulking surgery. Twenty-seven patients underwent rectosigmoid resection, whose status of MLN involvement was judged from hematoxylin and eosin (H&E) staining of resected specimens. The prognostic significance of clinicopathological characteristics, including MLN involvement, was evaluated using univariate and multivariate analyses. RESULTS: MLN involvement was detected in 14/85 patients with stage II-IV OC. Residual tumor status, cytology of ascites, and MLN involvement were independent prognostic factors for progression-free survival (PFS; p = 0.033, p = 0.014, and p = 0.008, respectively). When patients were classified into three groups (no MLN, one MLN, two or more MLNs), the number of MLNs involved corresponded to three distinct groups in PFS (p = 0.001). The 3-year cumulative incidence of liver metastasis of patients with MLN involvement was significantly higher than that of patients without MLN involvement (61.1% vs. 8.9%, p < 0.001). MLN involvement was significantly associated with liver metastasis of hematogenous origin (p < 0.001) compared with peritoneal disseminated origin. CONCLUSION: MLN involvement is an important prognostic factor in OC, predicting poor prognosis and liver metastasis of hematogenous origin.

DOI： 10.1245/s10434-021-09899-8

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DOI： 10.1245/s10434-021-09919-7

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Numerous epidemiological and histopathological studies support the notion that clear cell and endometrioid carcinomas derive from ovarian endometriosis. Accordingly, these histologic types are referred to as "endometriosis-associated ovarian cancer" (EAOC). Although the uterine endometrium is also considered an origin of endometriosis, the molecular mechanism involved in transformation of the uterine endometrium to EAOC via ovarian endometriosis has not yet been clarified. Recent studies based on high-throughput sequencing technology have revealed that cancer-associated gene mutations frequently identified in EAOC may exist in the normal uterine endometrial epithelium and ovarian endometriotic epithelium. The continuum of genomic alterations from the uterine endometrium to endometriosis and EAOC has been described, though the significance of cancer-associated gene mutations in the uterine endometrium or endometriosis remains unclear. In this review, we summarize current knowledge regarding the molecular characteristics of the uterine endometrium, endometriosis, and EAOC and discuss the molecular mechanism of cancer development from the normal endometrium through endometriosis in an effort to prevent EAOC.

DOI： 10.3390/cancers13061439

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Advanced-stage gynecologic cancer remains a life-threatening disease. Here, we present a protocol for establishment of stable in vitro 3D spheroid cells derived from human uterine endometrial and ovarian cancer tissues. The tumor-derived spheroid cells have cancer stem cell-related characteristics, including tumorigenesis, and can be used for biological and biochemical analyses and drug efficacy assays. Because these cells possess the biological characteristics of original human tumors, spheroid cells and spheroid-derived xenografts will have applications in personalized medicine in the future. For complete details on the use and execution of this protocol, please refer to Ishiguro et al. (2016) and Mori et al. (2019).

DOI： 10.1016/j.xpro.2021.100354

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Evidence from observational studies indicates that endometriosis and depression often co-occur. However, conflicting evidence exists, and the etiology as well as biological mechanisms underlying their comorbidity remain unknown. Utilizing genome-wide association study (GWAS) data, we comprehensively assessed the relationship between endometriosis and depression. Single nucleotide polymorphism effect concordance analysis (SECA) found a significant genetic overlap between endometriosis and depression (PFsig-permuted = 9.99 × 10-4). Linkage disequilibrium score regression (LDSC) analysis estimated a positive and highly significant genetic correlation between the two traits (rG = 0.27, P = 8.85 × 10-27). A meta-analysis of endometriosis and depression GWAS (sample size = 709,111), identified 20 independent genome-wide significant loci (P < 5 × 10-8), of which eight are novel. Mendelian randomization analysis (MR) suggests a causal effect of depression on endometriosis. Combining gene-based association results across endometriosis and depression GWAS, we identified 22 genes with a genome-wide significant Fisher's combined P value (FCPgene < 2.75 × 10-6). Genes with a nominal gene-based association (Pgene < 0.05) were significantly enriched across endometriosis and depression (Pbinomial-test = 2.90 × 10-4). Also, genes overlapping the two traits at Pgene < 0.1 (Pbinomial-test = 1.31 × 10-5) were significantly enriched for the biological pathways 'cell-cell adhesion', 'inositol phosphate metabolism', 'Hippo-Merlin signaling dysregulation' and 'gastric mucosa abnormality'. These results reveal a shared genetic etiology for endometriosis and depression. Indeed, additional analyses found evidence of a causal association between each of endometriosis and depression and at least one abnormal condition of gastric mucosa. Our study confirms the comorbidity of endometriosis and depression, implicates links with gastric mucosa abnormalities in their causal pathways and reveals potential therapeutic targets for further investigation.

DOI： 10.1007/s00439-020-02223-6

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Language：Japanese   Publisher：新潟産科婦人科学会  

症例1は80歳で、約2年前から子宮下垂感を自覚し、約1年前から排便時に直腸脱を認めるようになった。今回、Stage IVの子宮脱および完全直腸脱の診断で一期的根治手術を行う方針となり、腹腔鏡下にWells直腸後方固定術+子宮腟上部切断+両側付属器切除+シングルメッシュによる仙骨腟固定術を施行し、術後経過良好であった。症例2は78歳で、約2年前から子宮脱を自覚し、間欠的自己還納で対応していた。半年前に排尿困難感が出現し、手術目的で当科を紹介受診した。初回受診時は子宮脱のみであったが、2回目の診察で直腸脱の併発を認めた。今回、Stage IVの子宮脱および完全直腸脱の診断で症例1と同様の手術を行い、術後経過良好であった。

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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セプラフィルムは優れた癒着防止効果が報告されているが、腹腔鏡下手術での体腔内搬入や貼付操作に難渋することが多い。今回、セプラフィルムの操作にEndoロールを用いた方法を試行し、その有効性について従来法(リデューサーを用いる方法)と比較検討した。腹腔鏡下単純子宮全摘出術3例にEndoロールを使用した結果、3例とも充填が比較的簡便に途中で破損することなく可能であった。最も優れていた点は、5mmポートから挿入可能なため、カメラで確認しながら安全に体腔内搬入でき、周囲臓器にセプラフィルムが付着する前に、広がったままの状態で受け取ることにより貼付が容易な点であった。

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BACKGROUND: Mounting evidence for the role of distal fallopian tubes in the pathogenesis of epithelial ovarian cancer has led to opportunistic salpingectomy being increasingly performed at the time of benign gynecologic surgery. Opportunistic salpingectomy has now been recommended as best practice in the United States to reduce future risk of ovarian cancer even in low-risk women. Preliminary analyses have suggested that performance of opportunistic salpingectomy is increasing. OBJECTIVE: To examine trends in opportunistic salpingectomy in women undergoing benign hysterectomy and to determine how the publication of the tubal hypothesis in 2010 may have contributed to these trends. STUDY DESIGN: This is a population-based, retrospective, observational study examining the National Inpatient Sample between January 2001 and September 2015. Women younger than 50 years who underwent inpatient hysterectomy for benign gynecologic disease were grouped as hysterectomy alone vs hysterectomy with opportunistic salpingectomy. All women had ovarian conservation, and those with adnexal pathology were excluded. Linear segmented regression with log transformation was used to assess temporal trends. An interrupted time-series analysis was then used to assess the impact of the 2010 publication of the tubal hypothesis on opportunistic salpingectomy trends. A regression-tree model was constructed to examine patterns in the use of opportunistic salpingectomy. A binary logistic regression model was then fitted to identify independent characteristics associated with opportunistic salpingectomy. Sensitivity analysis was performed in women aged 50-65 years to further assess surgical trends in a wider age group. RESULTS: There were 98,061 (9.0%) women who underwent hysterectomy with opportunistic salpingectomy and 997,237 (91.0%) women who underwent hysterectomy alone without opportunistic salpingectomy. The rate at which opportunistic salpingectomy was being performed gradually increased from 2.4% to 5.7% between 2001 and 2010 (2.4-fold increase; P<.001), predicting a 7.0% rate of opportunistic salpingectomy in 2015. However, in 2010, the rate of opportunistic salpingectomy began to increase substantially and reached 58.4% by 2015 (10.2-fold increase; P<.001). In multivariable analysis, the largest change in the performance of opportunistic salpingectomy occurred after 2010 (adjusted odds ratio, 5.42; 95% confidence interval, 5.34-5.51; P<.001). In a regression-tree model, women who had a hysterectomy at urban teaching hospitals in the Midwest after 2013 had the highest chance of undergoing opportunistic salpingectomy during benign hysterectomy (76.4%). In the sensitivity analysis of women aged 50-65 years, a similar exponential increase in opportunistic salpingectomy was observed from 5.8% in 2010 to 55.8% in 2015 (9.8-fold increase; P<.001). CONCLUSION: Our study suggests that clinicians in the United States rapidly adopted opportunistic salpingectomy at the time of benign hysterectomy following the publication of data implicating the distal fallopian tubes in ovarian cancer pathogenesis in 2010. By 2015, nearly 60% of women had undergone opportunistic salpingectomy at benign hysterectomy.

DOI： 10.1016/j.ajog.2020.04.028

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：English   Publisher：(一社)日本癌学会  

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Whether germline (g) breast cancer susceptibility gene (BRCA) mutations are located within or outside the ovarian cancer cluster region (OCCR) (1380-4062 bp for gBRCA1, and between 3249-5681 bp and 6645-7471 bp for gBRCA2) may influence risk variations for ovarian cancers. This ad hoc analysis of the CHARLOTTE epidemiological study in Japan assessed the distribution of gBRCA1/2 mutations in patients with newly diagnosed ovarian cancer, and investigated an association between gBRCA1/2 mutation locations and ovarian cancer risk. Differences in patient background and clinical characteristics in subgroups stratified by gBRCA1/2 mutation locations were also evaluated. We analyzed the data of 93 patients (14.7%) from the CHARLOTTE study who were positive for gBRCA1/2 mutations. After excluding 16 cases with L63X founder mutation, 28 (65.1%) of gBRCA1 mutations were within the OCCR. Of 30 gBRCA2 mutations, 15 (50.0%) were within the OCCR. Of 27 patients (one patient excluded for unknown family history) with gBRCA1 mutations located in the OCCR, 11 (40.7%) had a family history of ovarian cancer; the proportion of patients with a family history of ovarian cancer and gBRCA1 mutations outside the OCCR was lower (13.3%). Sixty percent of patients with gBRCA1 mutations outside the OCCR had a family history of breast cancer; the proportion of patients with a family history of breast cancer and gBRCA1 mutations within the OCCR was relatively lower (33.3%). Understanding the mutation locations may contribute to more accurate risk assessments of susceptible individuals and early detection of ovarian cancer among gBRCA mutation carriers.

DOI： 10.1111/cas.14513

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ARID1A loss-of-function mutation accompanied by a loss of ARID1A protein expression is considered one of the most important driver events in endometriosis-associated ovarian cancer. Although our recent genomic study clarified that ARID1A loss-of-function mutations were detected in 13% of ovarian endometriosis, an association between the ARID1A mutation status and ARID1A protein expression in ovarian endometriosis remains unclear. We performed immunohistochemical staining for ARID1A in 78 ovarian endometriosis samples and 99 clear cell carcinoma samples. We revealed that not only 70 endometriosis samples without ARID1A mutations but also eight endometriosis samples with ARID1A loss-of-function mutations retained ARID1A protein expression. On the other hand, most of clear cell carcinomas with ARID1A loss-of-function mutations showed a loss of ARID1A protein expression. In particular, clear cell carcinoma samples which harbor multiple ARID1A loss-of-function mutations or both a single ARID1A loss-of-function mutation and ARID1A allelic imbalance lost ARID1A protein expression. However, ARID1A protein expression was retained in seven clear cell carcinomas with ARID1A loss-of-function mutations. These results suggest that a single ARID1A loss-of-function mutation is insufficient for ARID1A loss in ovarian endometriosis and some clear cell carcinoma. Further driver events may be needed for the malignant transformation of ovarian endometriosis with ARID1A loss-of-function mutations.

DOI： 10.1038/s41598-020-71273-7

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Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To examine trends, characteristics and outcomes of women who develop both ovarian and breast cancers. METHODS: This is a retrospective study examining the Surveillance, Epidemiology, and End Results Program from 1973 to 2013. Among ovarian cancer (n = 133,149) and breast cancer (n = 1,143,219) cohorts, women with both diagnoses were identified and temporal trends, tumor characteristics and survival were examined. RESULTS: There were 6446 women with both malignancies, representing 4.8% of the ovarian cancer cohort and 0.6% of the breast cancer cohort. Women with ovarian cancer who had secondary breast cancer were younger than those without secondary breast cancer early in the study period (52.3 versus 59.2 in 1973) but older in more recent years (68.5 versus 62.1 in 2013, P < 0.001). The number of breast cancer survivors who developed postcedent ovarian cancer decreased from 1.5 to 0.2% from 1979 to 2008 (relative risk reduction 90.0%, P < 0.05). Similarly, the number of ovarian cancer survivors who developed postcedent breast cancer decreased from 7.2 to 2.0% from 1973 to 2008 (relative risk reduction 72.4%, P < 0.05). Tumor characteristics were more likely to be favorable in women with ovarian cancer who developed postcedent breast cancer but unfavorable in those who had antecedent breast cancer (all, P < 0.05). Women with ovarian cancer who had secondary breast cancer had superior cause-specific survival compared to those who did not develop breast cancer regardless of breast cancer timing (P < 0.05). CONCLUSION: Our study demonstrated that the demographics of women who develop breast cancer and ovarian cancer have changed over time and diagnosis of secondary breast cancer after ovarian cancer has decreased.

DOI： 10.1007/s00404-020-05508-3

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Observational epidemiological studies indicate that endometriosis and migraine co-occur within individuals more than expected by chance. However, the aetiology and biological mechanisms underlying their comorbidity remain unknown. Here we examined the relationship between endometriosis and migraine using genome-wide association study (GWAS) data. Single nucleotide polymorphism (SNP) effect concordance analysis found a significant concordance of SNP risk effects across endometriosis and migraine GWAS. Linkage disequilibrium score regression analysis found a positive and highly significant genetic correlation (rG = 0.38, P = 2.30 × 10-25) between endometriosis and migraine. A meta-analysis of endometriosis and migraine GWAS data did not reveal novel genome-wide significant SNPs, and Mendelian randomisation analysis found no evidence for a causal relationship between the two traits. However, gene-based analyses identified two novel loci for migraine. Also, we found significant enrichment of genes nominally associated (Pgene < 0.05) with both traits (Pbinomial-test = 9.83 × 10-6). Combining gene-based p-values across endometriosis and migraine, three genes, two (TRIM32 and SLC35G6) of which are at novel loci, were genome-wide significant. Genes having Pgene < 0.1 for both endometriosis and migraine (Pbinomial-test = 1.85 ×10-°3) were significantly enriched for biological pathways, including interleukin-1 receptor binding, focal adhesion-PI3K-Akt-mTOR-signaling, MAPK and TNF-α signalling. Our findings further confirm the comorbidity of endometriosis and migraine and indicate a non-causal relationship between the two traits, with shared genetically-controlled biological mechanisms underlying the co-occurrence of the two disorders.

DOI： 10.3390/genes11030268

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Nature  

Background: Mutation of TP53 is the most frequent genetic alteration in high-grade serous ovarian cancer (HGSOC). The impact of hotspot mutations of TP53 and protein levels on patient outcomes in HGSOC has not been fully elucidated. Methods: The study population (n = 791) comprised of HGSOC samples with TP53 mutation from TCGA and other publicly available data. Univariate and multivariate cox proportional hazards regression analyses were used to select variables that were correlated with patient survival. Results: We assessed the effects of TP53 mutations based on type and individual hotspot mutations on patient outcomes in HGSOC. Only hotspot mutations were associated with outcomes. Three hotspot mutations: G266, Y163C, and R282, in aggregate were associated with a worsened overall and recurrence-free survival compared with other hotspot mutations (p &lt
0.0001 and p = 0.001), other non-hotspot missense mutations (p &lt
0.0001 and p = 0.008), truncated mutations (p &lt
0.0001 and p = 0.001), and all other mutations (p &lt
0.0001 and p = 0.001). Specific hotspot mutations were associated with different protein expression patterns consistent with different functions. Conclusions: This study provides evidence that individual TP53 hotspot mutations have different impact on HGSOC patient outcomes and potentially TP53 function. Thus the status of particular TP53 aberrations could influence response to therapy and selection of therapeutic agents.

DOI： 10.1038/s41416-019-0654-8

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Publishing type：Research paper (scientific journal)   Publisher：Asian Society of Gynecologic Oncology; Korean Society of Gynecologic Oncology and Colposcopy  

DOI： 10.3802/jgo.2019.30.e114

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Other Link： https://synapse.koreamed.org/DOIx.php?id=10.3802/jgo.2019.30.e114

Language：Japanese   Publisher：新潟県臨床細胞学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Uterine endometrial cancer is associated with poor survival outcomes in patients with advanced-stage disease. Here, we developed a three-dimensional cell cultivation method of endometrioid cancer stem-like cells with high aldehyde dehydrogenase (ALDH) activity from clinical specimens. ALDH inhibition synergized with paclitaxel to block cancer proliferation. In the clinical setting, high ALDH1A1 expression was associated with poor survival. A high level of ALDH correlated with an increase of glucose uptake, activation of the glycolytic pathway, and elevation of glucose transporter 1 (GLUT1). Blockade of GLUT1 inhibited characteristics of cancer stem cells. Similarly to ALDH inhibition, GLUT1 inhibition synergized with paclitaxel to block endometrial cancer proliferation. Our data indicated that ALDH-dependent GLUT1 activation and the resulting glycolytic activation are of clinical importance for both prognostic evaluation and therapeutic decision-making in endometrial cancer patients. In addition, the synergistic effects of taxane compounds and ALDH or GLUT1 inhibitors may serve as a new clinical treatment option for endometrial cancer.

DOI： 10.1016/j.stemcr.2019.08.015

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© 2019 Objective: To examine the association between ovarian conservation and oncologic outcome in surgically-treated young women with early-stage, low-grade endometrial cancer. Methods: This multicenter retrospective study examined women aged <50 with stage I grade 1–2 endometrioid endometrial cancer who underwent primary surgery with hysterectomy from 2000 to 2014 (US cohort n = 1196, and Japan cohort n = 495). Recurrence patterns, survival, and the presence of a metachronous secondary malignancy were assessed based on ovarian conservation versus oophorectomy. Results: During the study period, the ovarian conservation rate significantly increased in the US cohort from 5.4% to 16.4% (P = 0.020) whereas the rate was unchanged in the Japan cohort (6.3–8.7%, P = 0.787). In the US cohort, ovarian conservation was not associated with disease-free survival (hazard ratio [HR] 0.829, 95% confidence interval [CI] 0.188–3.663, P = 0.805), overall survival (HR not estimated, P = 0.981), or metachronous secondary malignancy (HR 1.787, 95% CI 0.603–5.295, P = 0.295). In the Japan cohort, ovarian conservation was associated with decreased disease-free survival (HR 5.214, 95% CI 1.557–17.464, P = 0.007) and an increased risk of a metachronous secondary malignancy, particularly ovarian cancer (HR 7.119, 95% CI 1.349–37.554, P = 0.021), but was not associated with overall survival (HR not estimated, P = 0.987). Ovarian recurrence or metachronous secondary ovarian cancer occurred after a median time of 5.9 years, and all cases were salvaged. Conclusion: Our study suggests that adoption of ovarian conservation in young women with early-stage low-grade endometrial cancer varies by population. Ovarian conservation for young women with early-stage, low-grade endometrial cancer may be potentially associated with increased risks of ovarian recurrence or metachronous secondary ovarian cancer in certain populations; nevertheless, ovarian conservation did not negatively impact overall survival.

DOI： 10.1016/j.ygyno.2019.08.007

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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DOI： 10.1016/j.ygyno.2019.05.014

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：English   Publisher：(公社)日本婦人科腫瘍学会  

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DOI： 10.3390/jcm8050714

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Retroperitoneal high-grade serous carcinoma (HGSC) is extremely rare and the origin remains unclear. We present a case of retroperitoneal HGSC and coexisting serous tubal intraepithelial carcinoma (STIC), which is considered as the main origin of ovarian HGSC. We reviewed the available literature and discussed about the origin of this rare disease. CASE PRESENTATION: A 58-year-old female with a 93 × 65 × 62 mm-solid tumor with a cystic part was located immediately dorsal to the rectum underwent bilateral salpingo-oophorectomy, total abdominal hysterectomy, and en bloc resection of the retroperitoneal tumor together with lower anterior resection of the rectum. Histological diagnosis was retroperitoneal HGSC and STIC at the right fallopian tube. Two deleterious somatic mutations in TP53 and BRCA2 genes were shared between retroperitoneal HGSC and STIC. CONCLUSIONS: In addition to clinical features in the previous reports, our genetic findings suggest the origin of retroperitoneal HGSC might be STIC.

DOI： 10.1186/s13000-019-0795-3

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

We explored the frequency of germline and somatic mutations in homologous recombination (HR)-associated genes in major histological types of ovarian cancer. We performed targeted sequencing to assess germline and somatic mutations of 16 HR-associated genes and 4 mismatch repair (MMR) genes among 207 ovarian cancer patients (50 high-grade serous carcinomas (HGSC), 99 clear cell carcinomas (CCC), 39 endometrioid carcinomas (EC), 13 mucinous carcinomas (MC), and 6 low-grade serous carcinomas (LGSC)). Germline or somatic mutations of HR-associated genes were detected in 44% of HGSC, 28% of CCC, 23% of EC, 16% of MC, and 17% of LGSC patients. The profile of HR-associated gene mutations was remarkably different among each histological type. Germline BRCA1/2 mutations were frequently detected in HGSC and were rarely observed in CCC, EC, and MC patients. ATM somatic mutation was more frequently detected in CCC (9%) and EC patients (18%) than in HGSC patients (4%). There was a positive correlation between MMR gene mutations and HR-associated gene mutations (p = 0.0072). Our findings might be useful in selection of ovarian cancer patients that should be treated with PARP inhibitors.

DOI： 10.1038/s41598-019-54116-y

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Language：English   Publishing type：Research paper (scientific journal)  

Primary ovarian sarcomas are extremely rare tumors, and their genomic and transcriptomic alterations remain to be elucidated. We performed whole exome sequencing of primary tumor and matched normal blood samples derived from one patient with ovarian undifferentiated small round cell sarcoma. We identified 8 nonsynonymous somatic mutations, and all mutations were missense or nonsense changes. Next, we performed RNA sequencing of the tumor sample and identified two in-frame fusion transcripts: MXD4-NUTM1 and ARL6-POT1. Most NUTM1 exons were retained in the MXD4-NUTM1 fusion transcript, and we confirmed an increase in NUTM1 mRNA and protein expression in tumor tissue. Further genomic and transcriptomic analyses might lead to the development of new therapeutic strategies based on the molecular characteristics of ovarian undifferentiated small round cell sarcoma.

DOI： 10.1002/gcc.22668

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Language：Japanese   Publisher：新潟産科婦人科学会  

腹腔鏡下子宮全摘術(TLH)を施行した既往帝王切開31例を対象とし、定型化した帝王切開術後の膀胱剥離法を開始前の3例(42〜51歳)と開始後28例(41〜62歳)であった。手術適応では、開始後で子宮体癌の症例数が11例と多かった。開腹への移行、膀胱損傷など、手技に関係する術中・術後の合併症は認めなかった。入院期間、手術時間に顕著な差は認めなかったが、出血量は開始後で少ない傾向にあった。

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Language：Japanese   Publisher：(公社)日本人間ドック学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(株)メジカルビュー社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Lippincott Williams and Wilkins  

Objectives: Cervical cancer is one of the most frequently diagnosed cancers in pregnancy. Our aim was to evaluate the safety and efficacy of abdominal radical trachelectomy (ART) for pregnant women with early-stage cervical cancer who strongly desire to preserve their pregnancies. Methods/Materials: A retrospective observational study was performed for stage IB1 cervical cancer patients who underwent ART or radical hysterectomy (RH) at our hospital between February 2013 and June 2017. We compared differences in perioperative findings and oncologic outcomes among ART during pregnancy (ART-DP), ART, and RH groups. Results: A total of 38 patients were included in this analysis. Six, 10, and 22 patients were assigned to the ART-DP, ART, and RH groups, respectively. There were no significant differences in the distribution of pathological TNM classifications, histology, tumor size, stromal invasion, and lymph-vascular space invasion among the 3 groups. The patients in the ART-DP group were younger than those in the RH group (P = 0.014). The ART-DP group was associated with more blood loss and prolonged surgery compared with the RH group (P = 0.017 and P = 0.014). The number of total lymph nodes in the ART-DP group was lower than that in the RH group (P = 0.036). However, there were no significant differences in age, surgical time, blood loss, or lymph node count between the ART-DP and ART groups. There were no significant differences in progression-free and overall survival times among the 3 groups, and no recurrence was observed in the ART-DP group. Conclusions: Abdominal radical trachelectomy may be a tolerable treatment option for pregnant women with early-stage cervical cancer who strongly desire a baby.

DOI： 10.1097/IGC.0000000000001218

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

Carcinoma-associated fibroblasts (CAFs) influence tumor initiation, progression, and metastasis within the tumor-associated stroma. This suggests that CAFs would be a potential target for tumor therapy. Here we found that Hydrogen peroxide-inducible clone-5 (Hic-5), also named transforming growth factor beta-1-induced transcript 1 protein (Tgfb1i1), was strongly induced in CAFs found in human colorectal cancer. To investigate the role of Hic-5 in CAFs, we isolated CAFs and the control counterpart normal fibroblasts (NFs) from human colorectal cancer and non-cancerous regions, respectively. Hic-5 was highly expressed in isolated human CAFs and strongly induced in NFs in culture by the supernatant from cultured colorectal cancer cells as well as cytokines such as TGF-β, IL-1β and stromal cell-derived factor 1 (SDF-1/CXCL12). Furthermore, tumor growth was inhibited in a co-culture assay with Hic-5 knockdown fibroblasts compared with control fibroblasts. To clarify the function and significance of Hic-5 in colorectal cancer in vivo, we utilized a mouse model of azoxymethane (AOM)-induced colorectal cancer using Hic-5-deficient mice. Lack of Hic-5 in CAFs completely prevented AOM-induced colorectal cancer development in the colon tissues of mice. Mechanistic investigation revealed that Hic-5 promoted the expression of lysyl oxidase and collagen I in human control counterpart fibroblasts. Taken together, these results demonstrate that Hic-5 in CAFs is responsible for orchestrating or generating a tumor-promoting stroma.

DOI： 10.1038/s41388-017-0033-y

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：Japanese   Publisher：北海道産科婦人科学会  

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Language：Japanese   Publisher：北海道産科婦人科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing  

Aim: We aimed to assess the accuracy and effectiveness of fetal cardiac screening for congenital heart disease (CHD) during the second trimester by general obstetricians in a non-selected population. Methods: In this multicenter, prospective cohort study of fetal cardiac screening, four-chamber and three-vessel views were recorded by obstetricians at 18–21 gestational weeks (GW). A total of 3005 fetuses that were scheduled for delivery at our institution were included. Results: Thirty-seven newborns were born with CHD (1.2%). On excluding 23 cases of ventricular septal defects, the prenatal detection rate of CHD was 42.8%. Although six cases (75.0%) of severe structural abnormality were diagnosed prenatally, the prenatal detection rate of valvular abnormalities was 0%. Conclusion: One-point ultrasound screening of the fetal heart using a combination of four-chamber and three-vessel views at 18–21 GW by general obstetricians in a non-selected population may be useful for detecting severe structural abnormalities but not valvular abnormalities. However, this limitation may be improved by conducting another fetal cardiac screening at approximately 30 GW along with the routine use of color Doppler.

DOI： 10.1111/jog.13472

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publisher：東北連合産科婦人科学会・北日本産科婦人科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

Epithelial ovarian cancer (EOC) is a deadly cancer, and its prognosis has not been changed significantly during several decades. To seek new therapeutic targets for EOC, we performed an in vivo dropout screen in human tumor xenografts using a pooled shRNA library targeting thousands of druggable genes. Then, in follow-up studies, we performed a second screen using a genome-wide CRISPR/Cas9 library. These screens identified 10 high-confidence drug targets that included well-known oncogenes such as ERBB2 and RAF1, and novel oncogenes, notably KPNB1, which we investigated further. Genetic and pharmacological inhibition showed that KPNB1 exerts its antitumor effects through multiphase cell cycle arrest and apoptosis induction. Mechanistically, proteomic studies revealed that KPNB1 acts as a master regulator of cell cycle-related proteins, including p21, p27, and APC/C. Clinically, EOC patients with higher expression levels of KPNB1 showed earlier recurrence and worse prognosis than those with lower expression levels of KPNB1. Interestingly, ivermectin, a Food and Drug Administration-approved antiparasitic drug, showed KPNB1-dependent antitumor effects on EOC, serving as an alternative therapeutic toward EOC patients through drug repositioning. Last, we found that the combination of ivermectin and paclitaxel produces a stronger antitumor effect on EOC both in vitro and in vivo than either drug alone. Our studies have thus identified a combinatorial therapy for EOC, in addition to a plethora of potential drug targets.

DOI： 10.1073/pnas.1705441114

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Background: Ovarian clear cell carcinoma (OCCC) is mostly resistant to standard chemotherapy that results in poor patient survival. To understand the genetic background of these tumours, we performed whole-genome sequencing of OCCC tumours.
Methods: Tumour tissue samples and matched blood samples were obtained from 55 Japanese women diagnosed with OCCC. Whole-genome sequencing was performed using the Illumina HiSeq platform according to standard protocols.
Results: Alterations to the switch/sucrose non-fermentable (SWI/SNF) subunit, the phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway, and the receptor tyrosine kinase (RTK)/Ras signalling pathway were found in 51%, 42%, and 29% of OCCC tumours, respectively. The 3-year overall survival (OS) rate for patients with an activated PI3K/Akt signalling pathway was significantly higher than that for those with inactive pathway (91 vs 40%, hazard ratio 0.24 (95% confidence interval (CI) 0.10-0.56), P = 0.0010). Similarly, the OS was significantly higher in patients with the activated RTK/Ras signalling pathway than in those with the inactive pathway (91 vs 53%, hazard ratio 0.35 (95% CI 0.13-0.94), P = 0.0373). Multivariable analysis revealed that activation of the PI3K/Akt and RTK/Ras signalling pathways was an independent prognostic factor for patients with OCCC.
Conclusions: The PI3K/Akt and RTK/Ras signalling pathways may be potential prognostic biomarkers for OCCC patients. Furthermore, our whole-genome sequencing data highlight important pathways for molecular and biological characterisations and potential therapeutic targeting in OCCC.

DOI： 10.1038/bjc.2017.228

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P&lt;5 x 10(-8)), implicating genes involved in sex steroid hormone pathways (FN1, CCDC170, ESR1, SYNE1 and FSHB). Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis. These results highlight novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offer unique opportunities for more targeted functional research efforts.

DOI： 10.1038/ncomms15539

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Sex-determining region Y-box 2 (SOX2) is an essential factor involved in the self-renewal and pluripotency of embryonic stem cells and has functions in cell survival and progression in many types of cancers. Here, we found that several endometrial cancer cell lines expressed SOX2, which was required for cell growth. Additionally, SOX2 overexpression regulated the expression of cyclin-dependent kinase inhibitor 1A (CDKN1A), and SOX2 specifically bound to p21 promoter DNA in endometrial cancer cell lines expressing SOX2. Expressions of SOX2 in endometrial cancer patients were significantly correlated with histological grade and poor prognosis. Moreover, low p21 together with high SOX2 expressions inadvanced endometrial cancer patients were associated with the most unfavorable outcomes of patients. These results indicated that simultaneous measurement of SOX2 and p21 expression in endometrial cancer patients may be a useful biomarker for patient prognosis.

DOI： 10.1111/cas.13196

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：English   Publisher：AMER SOC CLINICAL INVESTIGATION INC  

DOI： 10.1172/JCI91191

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：東北連合産科婦人科学会・北日本産科婦人科学会  

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Language：Japanese   Publisher：東北連合産科婦人科学会・北日本産科婦人科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

BACKGROUND & AIMS: High-throughput sequencing technologies have identified thousands of infrequently mutated genes in hepatocellular carcinomas (HCCs). However, high intratumor and intertumor heterogeneity, combined with large numbers of passenger mutations, have made it difficult to identify driver mutations that contribute to the development of HCC. We combined transposon mutagenesis with a high-throughput screen of a small-hairpin RNA (shRNA) library to identify genes and pathways that contribute to HCC development. METHODS: Sleeping beauty transposons were mobilized in livers of transgenic mice predisposed to develop hepatocellular adenoma and HCC owing to expression of the hepatitis B virus surface antigen. This whole-genome mutagenesis technique was used to generate an unbiased catalogue of candidate cancer genes (CCGs). Pooled shRNA libraries targeting 250 selected CCGs then were introduced into immortalized mouse liver cells and the cells were monitored for their tumor-forming ability after injection into nude mice. RESULTS: Transposon-mediated mutagenesis identified 1917 high-confident CCGs and highlighted the importance of Ras signaling in the development of HCC. Subsequent pooled shRNA library screening of 250 selected CCGs validated 27 HCC tumor-suppressor genes. Individual shRNA knockdown of 4 of these genes (Acaa2, Hbs1l, Ralgapa2, and Ubr2) increased the proliferation of multiple human HCC cell lines in culture and accelerated the formation of xenograft tumors in nude mice. The ability of Ralgapa2 to promote HCC cell proliferation and tumor formation required its inhibition of Rala and Ralb. Dual inhibition of Ras signaling via Ral and Raf, using a combination of small-molecule inhibitor RBC8 and sorafenib, reduced the proliferation of HCC cells in culture and completely inhibited their growth as xenograft tumors in nude mice. CONCLUSIONS: In a 2-step forward genetic screen in mice, we identified members of the Ral guanosine triphosphatase-activating protein pathway and other proteins as suppressors of HCC cell proliferation and tumor growth. These proteins might serve as therapeutic targets for liver cancer.

DOI： 10.1053/j.gastro.2016.04.040

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

OBJECTIVE: To examine the survival outcomes in women with endometrial cancer who were taking low-dose aspirin (81-100 mg/d).
METHODS: A multicenter retrospective study was conducted examining patients with stage I-IV endometrial cancer who underwent hysterectomy-based surgical staging between January 2000 and December 2013 (N=1,687). Patient demographics, medical comorbidities, medication types, tumor characteristics, and treatment patterns were correlated to survival outcomes. A Cox proportional hazard regression model was used to estimate adjusted hazard ratio for disease-free and disease-specific overall survival.
RESULTS: One hundred fifty-eight patients (9.4%, 95% confidence interval [CI] 8.8-11.9) were taking low-dose aspirin. Median follow-up time for the study cohort was 31.5 months. One hundred twenty-seven patients (7.5%) died of endometrial cancer. Low-dose aspirin use was significantly correlated with concurrent obesity, hypertension, diabetes mellitus, and hypercholesterolemia (all P&lt;.001). Low-dose aspirin users were more likely to take other antihypertensive, antiglycemic, and anticholesterol agents (all P&lt;.05). Low-dose aspirin use was not associated with histologic subtype, tumor grade, nodal metastasis, or cancer stage (all P&gt;.05). On multivariable analysis, low-dose aspirin use remained an independent prognostic factor associated with an improved 5-year disease-free survival rate (90.6% compared with 80.9%, adjusted hazard ratio 0.46, 95% CI 0.25-0.86, P=.014) and disease-specific overall survival rate (96.4% compared with 87.3%, adjusted hazard ratio 0.23, 95% CI 0.08-0.64, P=.005). The increased survival effect noted with low-dose aspirin use was greatest in patients whose age was younger than 60 years (5-year disease-free survival rates, 93.9% compared with 84.0%, P=.013), body mass index was 30 or greater (92.2% compared with 81.4%, P=.027), who had type I cancer (96.5% compared with 88.6%, P=.029), and who received postoperative whole pelvic radiotherapy (88.2% compared with 61.5%, P=.014). These four factors remained significant for disease-specific overall survival (all P&lt;.05).
CONCLUSION: Our results suggest that low-dose aspirin use is associated with improved survival outcomes in women with endometrial cancer, especially in those who are young, obese, with low-grade disease, and who receive postoperative radiotherapy.

DOI： 10.1097/AOG.0000000000001491

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

Epithelial-mesenchymal transition (EMT) is thought to contribute to metastasis and chemoresistance in patients with hepatocellular carcinoma (HCC), leading to their poor prognosis. The genes driving EMT in HCC are not yet fully understood, however. Here, we show that mobilization of Sleeping Beauty (SB) transposons in immortalized mouse hepatoblasts induces mesenchymal liver tumors on transplantation to nude mice. These tumors show significant down-regulation of epithelial markers, along with up-regulation of mesenchymal markers and EMT-related transcription factors (EMT-TFs). Sequencing of transposon insertion sites from tumors identified 233 candidate cancer genes (CCGs) that were enriched for genes and cellular processes driving EMT. Subsequent trunk driver analysis identified 23 CCGs that are predicted to function early in tumorigenesis and whose mutation or alteration in patients with HCC is correlated with poor patient survival. Validation of the top trunk drivers identified in the screen, including MET (MET proto-oncogene, receptor tyrosine kinase), GRB2-associated binding protein 1 (GAB1), HECT, UBA, and WWE domain containing 1 (HUWE1), lysine-specific demethylase 6A (KDM6A), and protein-tyrosine phosphatase, non-receptor-type 12 (PTPN12), showed that deregulation of these genes activates an EMT program in human HCC cells that enhances tumor cell migration. Finally, deregulation of these genes in human HCC was found to confer sorafenib resistance through apoptotic tolerance and reduced proliferation, consistent with recent studies showing that EMT contributes to the chemoresistance of tumor cells. Our unique cell-based transposon mutagenesis screen appears to be an excellent resource for discovering genes involved in EMT in human HCC and potentially for identifying new drug targets.

DOI： 10.1073/pnas.1606876113

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Recently, The Cancer Genome Atlas data revealed four molecular subtypes of high-grade serous ovarian carcinoma (HGSOC) exhibiting distinct prognoses. We developed four novel HGSOC histopathological subtypes by focusing on tumor microenvironment: mesenchymal transition, defined by a remarkable desmoplastic reaction; immune reactive by lymphocytes infiltrating the tumor; solid and proliferative by a solid growth pattern; and papilloglandular by a papillary architecture. Unsupervised hierarchical clustering revealed four clusters correlated with histopathological subtypes in both Kyoto and Niigata HGSOC transcriptome data sets (P &lt; 0.001). Gene set enrichment analysis revealed pathways enriched in our histopathological classification significantly overlapped with the four molecular subtypes: mesenchymal, immunoreactive, proliferative, and differentiated (P &lt; 0.0001, respectively). In 132 HGSOC cases, progression-free survival and overall survival were best in the immune reactive, whereas overall survival was worst in the mesenchymal transition (P &lt; 0.001, respectively), findings reproduced in 89 validation cases (P &lt; 0.05, respectively). The CLOVAR_MES_UP single-sample gene set enrichment analysis scores representing the mesenchymal molecular subtype were higher in paclitaxel responders than nonresponders (P = 0.002) in the GSE15622 data set. Taxane-containing regimens improved survival of cases with high MES_UP scores compared with nontaxane regimens (P &lt; 0.001) in the GSE9891 data set. Our novel histopathological classification of HGSOC correlates with distinct prognostic transcriptome subtypes. The mesenchymal transition subtype might be particularly sensitive to taxane.

DOI： 10.1016/j.ajpath.2015.12.029

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Genome-wide association studies (GWASs) have discovered numerous single nucleotide polymorphisms (SNPs) associated with human complex disorders. However, functional characterization of the disease-associated SNPs remains a formidable challenge. Here we explored regulatory mechanism of a SNP on chromosome 9p21 associated with endometriosis by leveraging "allele-specific" functional genomic approaches. By re-sequencing 1.29 Mb of 9p21 region and scrutinizing DNase-seq data from the ENCODE project, we prioritized rs17761446 as a candidate functional variant that was in perfect linkage disequilibrium with the original GWAS SNP (rs10965235) and located on DNase I hypersensitive site. Chromosome conformation capture followed by high-throughput sequencing revealed that the protective G allele of rs17761446 exerted stronger chromatin interaction with ANRIL promoter. We demonstrated that the protective allele exhibited preferential binding affinities to TCF7L2 and EP300 by bioinformatics and chromatin immunoprecipitation (ChIP) analyses. ChIP assays for histone H3 lysine 27 acetylation and RNA polymerase II reinforced the enhancer activity of the SNP site. The allele specific expression analysis for eutopic endometrial tissues and endometrial carcinoma cell lines showed that rs17761446 was a cis-regulatory variant where G allele was associated with increased ANRIL expression. Our work illuminates the allelic imbalances in a series of transcriptional regulation from factor binding to gene expression mediated by chromatin interaction underlie the molecular mechanism of 9p21 endometriosis risk locus. Functional genomics on common disease will unlock functional aspect of genotype-phenotype correlations in the post-GWAS stage.

DOI： 10.1371/journal.pgen.1005893

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Background: Ovarian and endometrial high-grade serous carcinomas (HGSCs) have similar clinical and pathological characteristics; however, exhaustive protein expression profiling of these cancers has yet to be reported.
Methods: We performed protein expression profiling on 14 cases of HGSCs (7 ovarian and 7 endometrial) and 18 endometrioid carcinomas (9 ovarian and 9 endometrial) using iTRAQ-based exhaustive and quantitative protein analysis.
Results: We identified 828 tumour-expressed proteins and evaluated the statistical similarity of protein expression profiles between ovarian and endometrial HGSCs using unsupervised hierarchical cluster analysis (P&lt;0.01). Using 45 statistically highly expressed proteins in HGSCs, protein ontology analysis detected two enriched terms and proteins composing each term: IMP2 and MCM2. Immunohistochemical analyses confirmed the higher expression of IMP2 and MCM2 in ovarian and endometrial HGSCs as well as in tubal and peritoneal HGSCs than in endometrioid carcinomas (P&lt;0.01). The knockdown of either IMP2 or MCM2 by siRNA interference significantly decreased the proliferation rate of ovarian HGSC cell line (P&lt;0.01).
Conclusions: We demonstrated the statistical similarity of the protein expression profiles of ovarian and endometrial HGSC beyond the organs. We suggest that increased IMP2 and MCM2 expression may underlie some of the rapid HGSC growth observed clinically.

DOI： 10.1038/bjc.2016.27

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

AimThe molecular pathogenesis of non-obstructive azoospermia (NOA) is unclear. Our aim was to identify the genetic susceptibility for NOA in Japanese men by using a combination of transcriptome network analysis and SNP genotyping.
Material and MethodsWe searched for candidate genes using RNA transcriptome network analysis of 2611 NOA-related genes that we had previously reported. We analyzed candidate genes for disease linkage with single nucleotide polymorphisms (SNP) in the genomes of 335 Japanese men with NOA and 410 healthy controls using SNP-specific real-time polymerase chain reaction TaqMan assays.
ResultsThree candidate genes (NR3C1, YBX2, and BCL2) were identified by the transcriptome network analysis, each with three SNP. Allele frequency analysis of the nine SNP indicated a significantly higher frequency of the NR3C1 rs852977 G allele in NOA cases compared with controls (corrected P = 5.7e-15; odds ratio = 3.20; 95% confidence interval, 2.40-4.26). The other eight candidate polymorphisms showed no significant association.
ConclusionThe NR3C1 rs852977 polymorphism is a potential marker for genetic susceptibility to NOA in Japanese men. Further studies are necessary to clarify the association between the NR3C1 polymorphism and alterations of glucocorticoid signaling pathway leading to male infertility.

DOI： 10.1111/jog.12877

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Recent advances in RNA-sequencing technology have enabled the discovery of gene fusion transcripts in the transcriptome of cancer cells. However, it remains difficult to differentiate the therapeutically targetable fusions from passenger events. We have analyzed RNA-sequencing data and DNA copy number data from 25 endometrial cancer cell lines to identify potential therapeutically targetable fusion transcripts, and have identified 124 high-confidence fusion transcripts, of which 69% are associated with gene amplifications. As targetable fusion candidates, we focused on three in-frame kinase fusion transcripts that retain a kinase domain (CPQ-PRKDC, CAPZA2-MET, and VGLL4-PRKG1). We detected only CPQ-PRKDC fusion transcript in three of 122 primary endometrial cancer tissues. Cell proliferation of the fusion-positive cell line was inhibited by knocking down the expression of wild-type PRKDC but not by blocking the CPQ-PRKDC fusion transcript expression. Quantitative real-time RT-PCR demonstrated that the expression of the CPQ-PRKDC fusion transcript was significantly lower than that of wild-type PRKDC, corresponding to a low transcript allele fraction of this fusion, based on RNA-sequencing read counts. In endometrial cancers, the CPQ-PRKDC fusion transcript may be a passenger aberration related to gene amplification. Our findings suggest that transcript allele fraction is a useful predictor to find bona-fide therapeutic-targetable fusion transcripts.

DOI： 10.1038/srep18657

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：東北連合産科婦人科学会・北日本産科婦人科学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER/PLENUM PUBLISHERS  

A previous genome-wide association study in European men identified four single nucleotide polymorphism (SNP) loci associated with male infertility. Our aim was to replicate, if possible, the association of these SNPs with Japanese male infertility.
We genotyped four SNPs (rs5911500, rs10246939, rs2059807, and rs11204546) in 517 Japanese patients with male infertility and 369 fertile controls using SNP-specific real-time polymerase chain reaction TaqMan assays. Subsequently, we divided patients with male infertility into azoospermia (n = 417) and oligospermia subgroups (n = 70).
The four SNPs previously identified in European men showed no significant association with collective male infertility in our Japanese cohort. However, allele frequency analysis did indicate a significantly higher frequency of the rs11204546 C allele of the OR2W3 gene in the oligospermia subset of infertility patients compared with controls (p = 0.0037; odds ratio = 1.74; 95 % confidence interval, 1.21-2.53).
Although this study was somewhat limited by overall sample size, the OR2W3 gene polymorphism rs11204546 was significantly associated with oligospermia in Japanese men, suggesting that OR2W3 might be involved in genetic susceptibility to Japanese male infertility as well as in European males.

DOI： 10.1007/s10815-015-0468-4

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Transcriptional profile-based subtypes of cancer are often viewed as identifying different diseases from the same tissue origin. Understanding the mechanisms driving the subtypes may be key in development of novel therapeutics but is challenged by lineage-specific expression signals. Using a t-test statistics approach, we compared gene expression subtypes across 12 tumor types, which identified eight transcriptional superclusters characterized by commonly activated disease pathways and similarities in gene expression. One of the largest superclusters was determined by the upregulation of a proliferation signature, significant enrichment in TP53 mutations, genomic loss of CDKN2A (p16(ARF)), evidence of increased numbers of DNA double strand breaks and high expression of cyclin B1 protein. These correlations suggested that abrogation of the P53-mediated apoptosis response to DNA damage results in activation of cell cycle pathways and represents a common theme in cancer. A second consistent pattern, observed in 9 of 11 solid tumor types, was a subtype related to an activated tumor-associated stroma. The similarity in transcriptional footprints across cancers suggested that tumor subtypes are commonly unified by a limited number of molecular themes.

DOI： 10.1038/onc.2014.216

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

When compared with other epithelial ovarian cancers, the clinical characteristics of ovarian clear cell adenocarcinoma (CCC) include 1) a higher incidence among Japanese, 2) an association with endometriosis, 3) poor prognosis in advanced stages, and 4) a higher incidence of thrombosis as a complication. We used high resolution comparative genomic hybridization (CGH) to identify somatic copy number alterations (SCNAs) associated with each of these clinical characteristics of CCC. The Human Genome CGH 244A Oligo Microarray was used to examine 144 samples obtained from 120 Japanese, 15 Korean, and nine German patients with CCC. The entire 8q chromosome (minimum corrected p-value: q = 0.0001) and chromosome 20q13.2 including the ZNF217 locus (q = 0.0078) were amplified significantly more in Japanese than in Korean or German samples. This copy number amplification of the ZNF217 gene was confirmed by quantitative real-time polymerase chain reaction (Q-PCR). ZNF217 RNA levels were also higher in Japanese tumor samples than in non-Japanese samples (P = 0.027). Moreover, endometriosis was associated with amplification of EGFR gene (q = 0.047), which was again confirmed by Q-PCR and correlated with EGFR RNA expression. However, no SCNAs were significantly associated with prognosis or thrombosis. These results indicated that there may be an association between CCC and ZNF217 amplification among Japanese patients as well as between endometriosis and EGFR gene amplifications.

DOI： 10.1371/journal.pone.0116977

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Language：Japanese   Publisher：新潟県医師会  

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Mobile elements comprise about half of the human genome. Three active mobile element families (L1, Alu, and SVA) possibly cause diseases such as cancer. We conducted mobile element insertion (MEI) profiling of 44 epithelial ovarian cancers using exome-sequencing data. We identified a total of 106 MEIs using the Mobster program, 8 of which were novel exonic MEIs.

DOI： 10.1038/hgv.2015.30

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DOI： 10.4172/2157-7420.1000180

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

Genome analysis which takes into account tumor purity leads to discovery of PTEN as a tumor suppressor gene in high-grade serous ovarian cancer.

DOI： 10.1186/s13059-014-0563-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Protein levels and function are poorly predicted by genomic and transcriptomic analysis of patient tumours. Therefore, direct study of the functional proteome has the potential to provide a wealth of information that complements and extends genomic, epigenomic and transcriptomic analysis in The Cancer Genome Atlas (TCGA) projects. Here we use reverse-phase protein arrays to analyse 3,467 patient samples from 11 TCGA 'Pan-Cancer' diseases, using 181 high-quality antibodies that target 128 total proteins and 53 post-translationally modified proteins. The resultant proteomic data are integrated with genomic and transcriptomic analyses of the same samples to identify commonalities, differences, emergent pathways and network biology within and across tumour lineages. In addition, tissue-specific signals are reduced computationally to enhance biomarker and target discovery spanning multiple tumour lineages. This integrative analysis, with an emphasis on pathways and potentially actionable proteins, provides a framework for determining the prognostic, predictive and therapeutic relevance of the functional proteome.

DOI： 10.1038/ncomms4887

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Background and objectives Aberrant DNA methylation contributes to the malignant phenotype in virtually all types of human cancer. This study explored the relationship between promoter methylation and inactivation of the DAPK1, FHIT, MGMT, and CDKN2A genes in cervical cancer.
Methods The promoter methylation of DAPK1, FHIT, MGMT, and CDKN2A was investigated by using a methylation-specific polymerase chain reaction in 53 specimens of cervical cancer (42 squamous cell carcinoma, 11 adenocarcinoma), 22 specimens of intraepithelial neoplasia tissues, and 24 control normal cervical tissue specimens. The correlation of promoter methylation with the clinicopathological features of cervical cancer was analyzed. The expressions of DAPK1, FHIT, MGMT, and CDKN2A were detected by measuring relative mRNA levels.
Results The promoter methylation of DAPK1, FHIT, MGMT, and CDKN2A in cervical cancer vs. intraepithelial neoplasia vs. normal cervical tissue was 75.5 vs. 31.8 vs. 4.2 % (P &lt; 0.0001), 66.0 vs. 59.1 vs. 25.0 % (p = 0.0033), 34.0 vs. 27.3 vs. 20.8 % (p = 0.76), and 17.0 vs. 31.8 vs. 8.3 % (p = 0.11), respectively. The methylation of the promoter region significantly decreased the expression of only DAPK1 (p = 0.03). The methylation rate of the DAPK1 gene promoter was significantly higher in cervical cancer tissues than in cervical intraepithelial neoplasia and normal cervical tissues.
Conclusion Promoter methylation may therefore lead to the inactivation of the DAPK1 gene, and may be related to the progression of cervical oncogenesis.

DOI： 10.1007/s10147-013-0530-0

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High-grade serous ovarian cancer (HGSOC) is the most aggressive histological type of epithelial ovarian cancer, which is characterized by a high frequency of somatic TP53 mutations. We performed exome analyses of tumors and matched normal tissues of 34 Japanese patients with HGSOC and observed a substantial number of patients without TP53 mutation (24%, 8/34). Combined with the results of copy number variation analyses, we subdivided the 34 patients with HGSOC into subtypes designated ST1 and ST2. ST1 showed intact p53 pathway and was characterized by fewer somatic mutations and copy number alterations. In contrast, the p53 pathway was impaired in ST2, which is characterized by abundant somatic mutations and copy number alterations. Gene expression profiles combined with analyses using the Gene Ontology resource indicate the involvement of specific biological processes (mitosis and DNA helicase) that are relevant to genomic stability and cancer etiology. In particular we demonstrate the presence of a novel subtype of patients with HGSOC that is characterized by an intact p53 pathway, with limited genomic alterations and specific gene expression profiles.

DOI： 10.1371/journal.pone.0114491

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Language：English   Publisher：AMER SOC CLINICAL INVESTIGATION INC  

DOI： 10.1172/JCI74035

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DOI： 10.1038/ng.2764

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Patients with ovarian cancer are at high risk of tumor recurrence. Prediction of therapy outcome may provide therapeutic avenues to improve patient outcomes. Using reverse-phase protein arrays, we generated ovarian carcinoma protein expression profiles on 412 cases from TCGA and constructed a PRotein-driven index of OVARian cancer (PROVAR). PROVAR significantly discriminated an independent cohort of 226 high-grade serous ovarian carcinomas into groups of high risk and low risk of tumor recurrence as well as short-term and long-term survivors. Comparison with gene expression-based outcome classification models showed a significantly improved capacity of the protein-based PROVAR to predict tumor progression. Identification of protein markers linked to disease recurrence may yield insights into tumor biology. When combined with features known to be associated with outcome, such as BRCA mutation, PROVAR may provide clinically useful predictions of time to tumor recurrence.

DOI： 10.1172/JCI68509

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Language：English   Publisher：Nature Publishing Group  

Our previous genome-wide association study has demonstrated that single-nucleotide polymorphisms (SNPs) located in intronic and downstream regions of IL1A (interleukin 1α) were associated with the risk of endometriosis. These SNPs on the genome-wide association study platform could be only surrogates for the true causal variant. Thus, we resequenced all the exons of IL1A in 377 patients with endometriosis and 457 healthy controls. We detected seven rare variants (minor allele frequency <0.01) and four common variants. All the rare variants were not associated with endometriosis. The four common variants (rs17561, rs1304037, rs2856836 and rs3783553) in IL1A were significantly associated with endometriosis (P=0.0024, 0.0024, 0.0014 and 0.0061, respectively). All the four SNPs were within a linkage disequilibrium block. Among them, only rs17561 was nonsynonymous (p.A114S), which has been reported to be associated with susceptibility to ovarian cancer. Taken together, we examined association between rs17561 and endometriosis in an independent validation data set (524 patients and 533 healthy controls) replicating significant association (P=4.0 × 10(-5); odds ratio (OR), 1.91; 95% confidence interval (CI), 1.41-2.61). Meta-analysis by combining results from the two stages strengthened the evidence of association (P=2.5 × 10(-7); OR, 1.90; 95% CI, 1.49-2.43). Our findings demonstrated that the nonsynonymous variant of IL1A might confer genetic susceptibility to endometriosis in Japanese population.

DOI： 10.1038/jhg.2013.32

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley Blackwell (Blackwell Publishing)  

Aim: Brain metastasis from ovarian cancer is a very rare phenomenon. BRCA1-related ovarian cancers show specific pathobiological profiles, advanced stage, and sensitivity to chemotherapeutic agents. However, no clear relationship to any known metastatic behavior has yet been found, so we examined the BRCA1 mutation and expression profiles in ovarian cancer cases with brain metastases. Material and Methods: We examined our clinical records of 340 ovarian cancer cases from 1983 to 2007 to ascertain cases with brain metastases. In the molecular genetic analyses, we performed loss of heterozygosity (LOH), direct sequence and immunohistochemical staining analysis of BRCA1. Results: We ascertained seven cases with brain metastases in 340 ovarian cancer cases (7/340 = 2.1%). Among the seven cases, three cases had ovarian and/or breast cancer patients in third-degree relatives. We detected four LOH-positive cases and a germline mutation of BRCA1 in two of the four cases. Furthermore, the remaining two cases showed absent staining of the BRCA1 protein. Therefore, four of seven cases with brain metastases were considered BRCA1-related ovarian cancers (4/7 = 57.1%). All four of the cases were serous adenocarcinoma. Conclusion: Our results suggest that the loss of BRCA1 function may be involved in the phenomenon of brain metastasis from ovarian cancer. Further molecular biologic analyses will be required for a better understanding of this rare phenomenon. © 2012 The Authors.

DOI： 10.1111/j.1447-0756.2012.01961.x

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Sekine M, Yoshihara K, Tanaka K, &lt;i&gt;Nihon rinsho. Japanese journal of clinical medicine&lt;/i&gt;, 2012, vol. 70 Suppl 4, pp. 469-474

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Endometriotic cells display invasive characteristics, despite their benign histological appearance. Recently, the epithelialmesenchymal transition, in which epithelial cells acquire mesenchymal and migratory properties, has attracted attention as a mechanism of tumor invasion. We aimed to investigate the association between endometriosis and polymorphisms of the E-cadherin gene, a central player in the epithelialmesenchymal transition, in Japanese women.
Twelve single-nucleotide polymorphisms (SNPs) in the E-cadherin gene were identified by real-time polymerase chain reaction using a TaqMan assay in 511 women with endometriosis (the majority in Stages III and IV) and 498 healthy controls.
Allele frequency analysis indicated that there was a marginally higher frequency of the rs4783689 C allele in women with endometriosis compared with controls (corrected P 0.007; odds ratio 1.37; 95 confidence interval, 1.141.64). No significant associations with endometriosis were found for the other 11 SNPs.
Although this study was limited by sample size, the E-cadherin gene polymorphism rs4783689 was marginally associated with endometriosis in the Japanese population, suggesting that E-cadherin might be involved in genetic susceptibility to endometriosis.

DOI： 10.1093/humrep/des080

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Language：Japanese   Publisher：(株)日本臨床社  

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Language：Japanese   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

Familial ovarian cancer occurs as part of two genetically distinct syndromes: hereditary breast and ovarian cancer (HBOC) and hereditary nonpolyposis colorectal cancer (HNPCC). HBOC caused by inherited mutations of BRCA1/2 and HNPCC caused by mismatch-repair genes are considered responsible for about 65 to 75% and 10 to 15% of familial ovarian cancers, respectively. Germline mutations of BRCA1 are considered responsible for about 50% of ovarian cancer families and 80% of breast-ovarian cancer families. BRCA2 mutations are less common than BRCA1 mutations in ovarian cancer families. A high proportion of serous adenocarcinomas at an advanced stage has been reported with BRCA-related ovarian cancers in several studies. It is controversial whether BRCA-related ovarian cancer patients carry a better prognosis despite the aggressive tu-mor-pathological characteristics of their disease, compared to sporadic cases. However, a good therapeutic response may be attributable to platinum-based chemotherapy. Recently in Japan, gene testing of BRCA1/2 has been available as a routine clinical test for diagnosing ovarian cancer families. Because the mutation spectrum of BRCA1/2 in Japanese was different from that of non-Ashkenazi individuals, the clinical application of BRCA1/2 gene testing for Japanese has been advocated. Approximately 1-5% of ovarian cancer patients in Japan are thought to have a family history of breast and/or ovarian cancer. The prevalence of deleterious mutations of BRCA1/2 in Japanese was reportedly significantly higher than that of non-Ashkenazi individuals despite the low frequency of familial cases in Japan. Although the age at diagnosis of ovarian cancers with BRCA1/2 mutation in the United States was earlier than those of the sporadic cases, there were no differences among Japanese. These results suggest that clinical and genetic aspects of BRCA-related ovarian cancer of the Japanese are different from those of Caucasians. A serious issue in this field is how the results will lead to a basis for the clinical application of a cancer prevention strategy targeting BRCA mutation carriers in Japanese.

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

We investigated characteristics of germline copy number variations (CNV) in BRCA1-associated ovarian cancer patients by comparing them to CNVs present in sporadic ovarian cancer patients. Germline CNVs in 51 BRCA1-associated, 33 sporadic ovarian cancer patients, and 47 healthy women were analyzed by both signal intensity and genotyping data using the Affymetrix Genome-Wide Human SNP Array 6.0. The total number of CNVs per genome was greater in the sporadic group (median 26, range 12-34) than in the BRCA1 group (median 21, range 11-35; post hoc P &lt; 0.05) or normal group (median 20, range 7-32; post hoc P &lt; 0.05). While the number of amplifications per genome was higher in the sporadic group (median 13, range 7-26) than in the BRCA1 group (median 8, range 3-23; post hoc P &lt; 0.001), the number of deletions per genome was higher in the BRCA1 group (median 12, range 6-24) than in the sporadic group (median 9, range 3 17; post hoc P &lt; 0.01). In addition, 31 previously unknown CNV regions were present specifically in the BRCA1 group. When we performed pathway analysis on the 241 overlapping genes mapped to these novel CNV regions, the &apos;purine metabolism&apos; and &apos;14-3-3-mediated signaling&apos; pathways were over-represented (Fisher&apos;s exact test, P &lt; 0.01). Our study shows that there are qualitative differences in genomic CNV profiles between BRCA1-associated and sporadic ovarian cancer patients. Further studies are necessary to clarify the significance of the genomic CNV profile unique to BRCA1-associated ovarian cancer patients. (C) 2010 Wiley-Liss, Inc.

DOI： 10.1002/gcc.20841

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Ovarian cancer, one of the most common gynecological malignancies, has an aggressive phenotype. It is necessary to develop novel and more effective treatment strategies against advanced disease. Protein tyrosine kinases (PTKs) play an important role in the signal transduction pathways involved in tumorigenesis, and represent potential targets for anticancer therapies. In this study, we performed cDNA subtraction following polymerase chain reaction (PCR) using degenerate oligonucleotide primers to identify specifically overexpressed PTKs in ovarian cancer. Three PTKs, janus kinase 1, insulin-like growth factor 1 receptor, and discoidin domain receptor 1 (DDR1), were identified and only DDR1 was overexpressed in all ovarian cancer tissues examined for the validation by quantitative real-time PCR. The DDR1 protein was expressed in 63% (42/67) of serous ovarian cancer tissue, whereas it was undetectable in normal ovarian surface epithelium. DDR1 was expressed significantly more frequently in high-grade (79%) and advanced stage (77%) tumors compared to low-grade (50%) and early stage (43%) tumors. The expression of the DDR1 protein significantly correlated with poor disease-free survival. Although its functional role and clinical utility remain to be examined in future studies, our results suggest that the expression of DDR1 may serve as both a potential biomarker and a molecular target for advanced ovarian cancer.

DOI： 10.3390/ijms12020971

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Other Link： http://orcid.org/0000-0002-2254-3378

Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Objective: Our aim was to investigate the association between fetal growth and cerebrovascular resistance in fetuses with congenital heart disease (CHD). Methods: Fetal echo-cardiography was performed to measure the biparietal diameter, abdominal circumference, femur length, estimated fetal body weight, middle cerebral artery (MCA) resistance index (RI) and umbilical artery (UA) RI in 44 fetuses with CHD and 140 normal fetuses at a gestational age of 28-34 weeks. Results: Fetuses with CHD exhibited significantly lower values for femur length, estimated fetal body weight at the third trimester, body weight, length, and chest circumference at birth than normal controls. The percentages of fetuses showing MCA RI values &lt;10th percentile and UA RI values &gt;90th percentile were significantly higher in the CHD group than in the control group. However, there were no significant differences in any biometric parameters measured between cases with MCA RI values &gt;= 10th percentile and values &lt;10th percentile. Conclusions: Growth restriction and blood flow changes were observed significantly more frequently in fetuses with CHD than in those without CHD. Further studies are necessary to clarify the association between fetal growth and dynamic changes in fetal circulation. Copyright (C) 2011 S. Karger AG, Basel

DOI： 10.1159/000330202

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

To identify susceptibility genes for endometriosis in Japanese women, genome-wide association (GWA) analysis was performed using two case-control cohorts genotyped with the Affymetrix Mapping 500K Array or Genome-Wide Human SNP Array 6.0. In each of the two array cohorts, stringent quality control (QC) filters were applied to newly obtained genotype data, together with previously analyzed data from the Japanese Integrated Database Project. After QC-based filtering of samples and single nucleotide polymorphisms (SNPs) in each cohort, 282 838 SNPs in both genotyping platforms were tested for association with endometriosis using a meta-analysis of the two GWA studies with 696 patients with endometriosis and 825 controls. The meta-analysis revealed that a common susceptibility locus conferring a large effect on the disease risk was unlikely. On the other hand, an excess of SNPs with P-values &lt;10(-4) (36 vs 28 SNPs expected by chance) was observed in the meta-analysis. Of note, four of the top five SNPs with P-values &lt;10(-5) were located in and around IL1A (interleukin 1 alpha), which might be a functional candidate gene for endometriosis. Further studies with larger case-control cohorts will be necessary to elucidate the genetic risk factors. Journal of Human Genetics (2010) 55, 816-821; doi:10.1038/jhg.2010.118; published online 16 September 2010

DOI： 10.1038/jhg.2010.118

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Objective. Obesity is a well-known risk factor for the development of endometrial cancer. Elevated endogenous estrogen and insulin resistance are recognized to be major factors that link obesity and cancer development. However, there is increasing evidence that the adipokines adiponectin and leptin, which are directly produced in adipose tissue, impact several obesity-related cancers. The purpose of the current study was to investigate the relationships of the concentration of leptin, adiponectin, and the leptin-to-adiponectin ratio (L/A ratio) with the endometrial cancer risk in postmenopausal female subjects.
Methods. A case-control study was performed in 146 postmenopausal female subjects with endometrial cancer and 150 control subjects with no history of cancer. The serum levels of the adipokines leptin and adiponectin were measured, and the associations of these adipokines and the L/A ratios with the endometrial cancer risk were analyzed.
Results. The leptin levels and the L/A ratios were significantly higher in the incident cases of endometrial cancer (8.2 +/- 0.5, 2.05 +/- 1.08 ng/ml) than in the controls subjects (4.5 +/- 0.5, 0.98 +/- 0.18, P&lt;0.0001), whereas the adiponectin levels were significantly lower in the incident cases (6.2 +/- 0.4 mu g/ml) than in the control subjects (9.0 +/- 0.4 mu g/ml, P&lt;0.0001). For the incident cases, the serum levels of the adipokines were significantly correlated with the patient body mass index (BMI) (P&lt;0.001 for leptin, P&lt;0.05 for adiponectin), and the leptin levels and the L/A ratios were significantly correlated with the homeostasis model assessment ratio (HOMA-R) and the fasting insulin levels (P&lt;.001). Higher L/A ratios were found to be significantly associated with an increased risk of endometrial cancer [OR (95% Cl) for the top vs. the bottom tertile of the L/A ratio was 6.0 (3.2-11.9), P-value&lt;0.0001]. Moreover, the ORs of the L/A ratios were higher than those of leptin or adiponectin alone. The association of the L/A ratios with endometrial cancer risk remained after adjusting for the obesity indices, hypertension, and presence of diabetes mellitus.
Conclusion. The present results suggested that the L/A ratio was independently associated with an increased risk for endometrial cancer development. Additional research will elucidate the molecular mechanisms by which these adipokines are associated with the development of endometrial cancer. (C) 2010 Published by Elsevier Inc.

DOI： 10.1016/j.ygyno.2010.07.007

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Background: Advanced-stage ovarian cancer patients are generally treated with platinum/taxane-based chemotherapy after primary debulking surgery. However, there is a wide range of outcomes for individual patients. Therefore, the clinicopathological factors alone are insufficient for predicting prognosis. Our aim is to identify a progression-free survival (PFS)-related molecular profile for predicting survival of patients with advanced-stage serous ovarian cancer.
Methodology/Principal Findings: Advanced-stage serous ovarian cancer tissues from 110 Japanese patients who underwent primary surgery and platinum/taxane-based chemotherapy were profiled using oligonucleotide microarrays. We selected 88 PFS-related genes by a univariate Cox model (p &lt; 0.01) and generated the prognostic index based on 88 PFS-related genes after adjustment of regression coefficients of the respective genes by ridge regression Cox model using 10-fold cross-validation. The prognostic index was independently associated with PFS time compared to other clinical factors in multivariate analysis [hazard ratio (HR), 3.72; 95% confidence interval (CI), 2.66-5.43; p &lt; 0.0001]. In an external dataset, multivariate analysis revealed that this prognostic index was significantly correlated with PFS time (HR, 1.54; 95% CI, 1.20-1.98; p = 0.0008). Furthermore, the correlation between the prognostic index and overall survival time was confirmed in the two independent external datasets (log rank test, p = 0.0010 and 0.0008).
Conclusions/Significance: The prognostic ability of our index based on the 88-gene expression profile in ridge regression Cox hazard model was shown to be independent of other clinical factors in predicting cancer prognosis across two distinct datasets. Further study will be necessary to improve predictive accuracy of the prognostic index toward clinical application for evaluation of the risk of recurrence in patients with advanced-stage serous ovarian cancer.

DOI： 10.1371/journal.pone.0009615

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：J REPROD MED INC  

OBJECTIVE: To examine the possible association of adiponectin (ADIPOQ), adiponectin receptor (ADI-POR1/2) gene polymorphisms with polycystic ovary syndrome (PCOS) and their influence on insulin resistance in Japanese women with PCOS.
STUDY DESIGN: Six single nucleotide polymorphisms (SNPs) in ADIPOQ and ADIPOR1/2 were genotyped in 59 infertile Japanese women with PCOS and 97 healthy Japanese controls. In addition, the association between the genotype and allele frequencies of these SNPs and the clinical phenotypes Was analyzed in PCOS patients.
RESULTS: There was no significant difference in the genotype and allele frequencies of the 6 SNPs between PCOS patients and controls. In the PCOS group, women With the GG genotype of 45T&gt;G of ADIPOQ had a significantly higher score in the homeostasis model assessment for insulin resistance,fasting blood sugar and insulin level than those With other genotypes. Furthermore, a statistically significant difference in the genotype frequency of 45T&gt;G polymorphism was observed between. PCOS subjects With insulin resistance (n = 38) and controls (P = 0.011).
CONCLUSION: The 6 SNPs of ADIPOQ and ADI-POR1/2 were not associated With a risk of PCOS. However, the 45T&gt;G SNP in the ADIPOQ may be related to insulin resistance in Japanese women with PCOS. (J Reprod Med 2009;54: 669-674)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

To elucidate the mechanisms of rapid progression of serous ovarian cancer, gene expression profiles from 43 ovarian cancer tissues comprising eight early stage and 35 advanced stage tissues were carried out using oligonucleotide microarrays of 18 716 genes. By non-negative matrix factorization analysis using 178 genes, which were extracted as stage-specific genes, 35 advanced stage cases were classified into two subclasses with superior (n = 17) and poor (n = 18) outcome evaluated by progression-free survival (log rank test, P = 0.03). Of the 178 stage-specific genes, 112 genes were identified as showing different expression between the two subclasses. Of the 48 genes selected for biological function by gene ontology analysis or Ingenuity Pathway Analysis, five genes (ZEB2, CDH1, LTBP2, COL16A1, and ACTA2) were extracted as candidates for prognostic factors associated with progression-free survival. The relationship between high ZEB2 or low CDH1 expression and shorter progression-free survival was validated by real-time RT-PCR experiments of 37 independent advanced stage cancer samples. ZEB2 expression was negatively correlated with CDH1 expression in advanced stage samples, whereas ZEB2 knockdown in ovarian adenocarcinoma SKOV3 cells resulted in an increase in CDH1 expression. Multivariate analysis showed that high ZEB2 expression was independently associated with poor prognosis. Furthermore, the prognostic effect of E-cadherin encoded by CDH1 was verified using immunohistochemical analysis of an independent advanced stage cancer samples set (n = 74). These findings suggest that the expression of epithelial-mesenchymal transition-related genes such as ZEB2 and CDH1 may play important roles in the invasion process of advanced stage serous ovarian cancer. (Cancer Sci 2009).

DOI： 10.1111/j.1349-7006.2009.01204.x

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

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Language：Japanese   Publisher：(株)メディカルレビュー社  

次世代シークエンサーの普及により、がんのゲノム異常を網羅的に調べることが容易になった。The Cancer Genome Atlas(TCGA)に代表されるゲノム研究により、卵巣がんのゲノム異常も明らかとなり、がんゲノム情報の臨床応用が進められている。特に高異型度漿液性がんではBRCA1/2をはじめとする相同組換え修復関連遺伝子の異常を約半数で認めており、複数の臨床試験でPARP阻害薬の有効性が示されている。本稿では、がんゲノム情報に基づいた卵巣がんに対するPARP阻害薬選択について概説する。(著者抄録)

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Language：Japanese   Publisher：日本エンドメトリオーシス学会  

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Language：Japanese   Publisher：日本婦人科病理学会  

卵巣癌は、The Cancer Genome Atlasの第1期に解析対象になった疾患で、オミックス解析が進んでいる癌種の一つである。本稿では、これまでに報告されている卵巣癌ゲノム解析の結果を、1)高異型度漿液性癌、2)粘液性癌、3)内膜症関連卵巣癌、の各項目で整理した。さらに、当科で取り組んでいる「正常子宮内膜のゲノム異常に注目した子宮内膜症・内膜症関連卵巣癌の病態解明」研究の成果を報告した。ゲノム解析のため、卵巣子宮内膜症13症例から子宮内膜症上皮、また子宮摘出が行われた卵巣子宮内膜症5症例と内膜症以外の婦人科良性疾患症例から正常子宮内膜上皮を採取し、DNAを抽出して全エクソンシークエンスを行った。その結果、内膜症上皮と子宮内膜上皮ともに遺伝子を多数認めた。また、癌関連遺伝子(KRAS、PIK3CA、FBXW7、ARHGAP35、PPP2R1A、PIK3R1、PTPN13)変異は内膜症上皮だけでなく子宮内膜上皮にも存在することが明らかになった。KRASおよびPIK3CAの変異アリル頻度は子宮内膜上皮に比して内膜症上皮で有意に高く、KRAS変異やPIK3CA変異を持つ内膜症上皮細胞がクローン性に増殖していることが示唆された。

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Language：Japanese   Publisher：(公財)上原記念生命科学財団  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

著者らは「オミックスデータ解析から婦人科悪性腫瘍の発生を探る」をテーマに掲げ、日本人に多いとされる内膜症関連卵巣癌のゲノム解析を行った。その結果、これまで内膜症関連卵巣癌で指摘されていた遺伝子変異であるPIK3CAやKRASはすでに子宮内膜上皮や卵巣子宮内膜症上皮に存在することが明らかとなった。子宮内膜上皮が癌関連遺伝子変異を有することで、月経血逆流による異所への移動・生着および増殖に有利に働き、子宮内膜症の発症につながると考えられた。そして、癌関連遺伝子変異を有する内膜症上皮に、ドライバー遺伝子の異常が加わることで癌が発生すると推察された。

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(公社)日本人間ドック学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2017-529

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2017-411

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Language：Japanese   Publisher：新潟医学会  

子宮頸癌の原因としてヒトパピローマウイルス(HPV)感染が特定されたにもかかわらず、本邦においてHPVワクチンの普及は進んでおらず、子宮頸癌制圧までの道のりは厳しい状況にある。また本邦において子宮頸癌検診の受診率は低く、子宮頸癌罹患率は20〜30歳代で急激に増加し、死亡数も減少から増加に転じており、予後改善につながる新規治療戦略の構築は急務である。ゲノム解析技術の進歩により、癌ゲノム異常を網羅的に探索することが可能となり、新しい治療標的の同定を目指して、様々な癌でゲノム・トランスクリプトーム・プロテオミクス解析が行われている。癌ゲノム異常のうち、融合遺伝子の同定は、癌化メカニズムの解明につながると同時に、治療標的として重要な意義を持つ。非小細胞性肺癌の約5%で同定されるEML4-ALK融合遺伝子は、代表的な治療標的融合遺伝子であり、その阻害剤はすでに臨床応用され、高い奏効率を示すことが知られている。しかし子宮頸癌領域では、これまで大規模網な網羅的融合遺伝子の検索は行われておらず、治療標的融合遺伝子の同定には至っていない。そこで筆者らは、子宮頸癌における新規治療標的融合遺伝子を同定することを目的とし、子宮頸癌に対するトランスクリプトーム解析を進めている。本シンポジウムでは、融合遺伝子について概説し、筆者らが行っている婦人科癌領域における融合遺伝子研究を紹介する。(著者抄録)

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(株)最新医学社  

The Cancer Genome Atlas(TCGA)は,婦人科三大悪性疾患である卵巣がん,子宮体がん,子宮頸がんの統合ゲノム解析を完了している.疾患当たり約500例を対象とした大規模研究であり,その結果は百科事典的にまとめられている.しかし実際に個別化治療を考えると,統合ゲノム解析の結果が婦人科の実臨床に応用された例はいまだなく,橋渡しがうまくいっているとは言えない.本稿では,ゲノム解析の結果から実臨床に応用可能な情報を抽出し,整理することとする.(著者抄録)

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Other Link： http://search.jamas.or.jp/link/ui/2017201267

Language：Japanese   Publisher：新潟産科婦人科学会  

婦人科悪性腫瘍手術の周術期予防的抗菌薬投与について検討した。開腹による悪性腫瘍根治術を施行し、術後の抗生剤を使用せず周術期のみセファゾリン(CEZ)を使用した140例を対象とした。手術部位感染(SSI)を発症した感染例6例、非感染例134例であった。6例でSSIを認めたが、6時間以上の手術20例では3例でSSIを発症した。術後1日目のCRP値は、感染群で高値の傾向があった。発症率は、腸管切除施行83%、施行していない32%であったが、有意差を認めなかった。抗菌剤投与が適正に行われていた60例中1例、適正投与されなかった44例中3例でSSIを発症していたが、有意差は認めなかった。腸管切除を施行した12例のうち8例に3時間毎の適正な抗菌剤投与が施行された。

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Other Link： http://search.jamas.or.jp/link/ui/2016398677

Language：Japanese   Publisher：日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=456638

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=456622

Language：Japanese   Publisher：新潟産科婦人科学会 ; 2011-  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：Japanese   Publisher：(株)診断と治療社  

次世代シーケンサーの普及により、遺伝子変異やコピー数変化といったゲノム解析が積極的に行われる時代になり、トランスクリプトーム解析の意義や位置づけが大きく変わろうとしている。トランスクリプトームは、細胞内の全転写産物を意味するが、本稿ではメッセンジャーRNAに焦点を当てて臨床検体を用いた婦人科がんのトランスクリプトーム解析について概説し、その臨床応用の可能性について紹介する。(著者抄録)

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Other Link： http://search.jamas.or.jp/link/ui/2014229547

Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(株)癌と化学療法社  

家族性卵巣癌全体でのBRCA1/2遺伝子変異は65〜75%、Mismatch Repair(MMR)遺伝子変異[Lynch症候群あるいはHereditary Non-Polyposis Colorectal Cancer(HNPCC)]は10〜15%とされている。BRCA2の関与はBRCA1より明らかに少なく、BRCA1変異が全体の約半数に認められる。乳癌患者を含む乳癌卵巣癌家系では、BRCA1変異を有する頻度がさらに高い。BRCA関連卵巣癌の臨床的特徴として漿液性腺癌、進行例が多いとされる。予後に関して一定の見解は得られていないが、散発性に比べ抗癌剤感受性が高い可能性が示唆されている。わが国では、近年になってBRCA遺伝子解析が臨床の場で積極的に行われはじめ、遺伝子変異型のプロファイルがアシュケナジユダヤ人を除いた欧米人とも明らかに異なることがわかり、日本人に対する効率的な遺伝子検査が提唱されている。わが国における卵巣癌全体での家族性の頻度は1〜5%と低いものの、家族性乳癌卵巣癌でのBRCA遺伝子変異検出率は欧米人と比較して有意に高いことが示されている。欧米でのBRCA関連卵巣癌は発症年齢が低いとされるが、本邦では有意差を認めないとする報告があることからも、遺伝的・臨床的両面において欧米との差違が推測される。これらの基礎データをどのようにして薬剤による化学予防や予防手術に発展させ、遺伝子変異を有する未発症キャリアでの予防医療に結び付けていくかがこれからの大きな課題となるであろう。(著者抄録)

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J00296&link_issn=&doc_id=20120507460004&doc_link_id=%2Fab8gtkrc%2F2012%2F003904%2F004%2F0506-0511%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2012%2F003904%2F004%2F0506-0511%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=448443

Language：Japanese   Publisher：日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=448379

Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=445864

Language：Japanese   Publisher：日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=447245

Language：Japanese   Publisher：日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=447241

Language：Japanese   Publisher：日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=444574

Language：Japanese   Publisher：日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=445453

Language：English   Publisher：日本癌学会  

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Other Link： http://hdl.handle.net/10191/28474

Language：Japanese   Publisher：日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=443034

Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：新潟医学会  

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Other Link： http://search.jamas.or.jp/link/ui/2008037600

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=439170

Language：Japanese   Publisher：鶴岡市立荘内病院  

42歳女。2妊2産。患者は突然の下腹部痛・目眩・ふらつき・嘔気・嘔吐があり、軽快しないため救急外来へ受診となった。来院時、出血性ショックの状態で、腹部超音波および画像所見では腹腔内の多量の腹水、超新生児頭大の骨盤内腫瘤を認めた。腫瘤周囲やダグラス窩には凝血塊と思われるhigh density areaがみられ、子宮または卵巣からの出血が疑われた。貧血の進行も認められたため緊急開腹手術が行なわれたが、2500mlにも及ぶ腹腔内出血が確認され、出血は漿膜下筋腫の表在血管の破綻によるものであった。治療として腹式子宮全摘術を施行した結果、患者は貧血の進行はなく、術後28日目に退院となった。

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

44歳初産婦。患者は妊娠32週4日の妊婦健診にて軽度の妊娠高血圧腎症を認め、入院となった。入院後、血圧の上昇、胃痛、嘔気を認め、妊娠33週6日にHELLP症候群およびreversible posterior leukoencephalopathy syndrome(RPLS)と診断され、緊急帝王切開術を行い、1625gの女児を娩出した。しかし、術後15時間後より強直性間代性発作が出現し、脳MRIにて両側後頭頭頂葉を中心に著明な脳浮腫を認めた。ICUにて昇圧剤持続静注、グリセリン製剤、ステロイド投与を開始したが、術後1日目に急性腎不全を生じ、持続血液濾過透析を開始した。術後2日目より視力障害、精神症状を認め、術後3日目には著明な胸水貯留とともに急性呼吸不全が出現し、持続胸腔ドレナージを施行したところ、術後8日目には全身状態は改善し、視力障害、精神障害も軽快した。術後36日目の脳MRIでは異常は認めず、現在は後遺症なく回復している。

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Language：Japanese   Publisher：(株)診断と治療社  

約20年間の脳動静脈奇形(AVM))合併妊娠8例9妊娠について後方視的に検討した.発症頻度は0.096%で,初発症状は頭蓋内出血7例,痙攣1例であった.症例1,2は今回妊娠時に初回出血,症例3は前回妊娠時に出血,症例4,5は非妊娠時に出血し,今回の妊娠時に再出血した.症例1は神経症状が重かったため血腫除去,脳内ドレナージを行い,症例2〜5は神経症状が軽かったため保存的に管理し妊娠を継続した.症例1は初回分娩後に塞栓術とγナイフによる治療を行い,症例3は分娩後,未治療であったが,両症例とも次回の妊娠時では再出血なく経過した.妊娠中に再出血した症例4,5は妊娠前にAと診断されていたが,症例4はAVMに対して未治療であり,症例5は妊娠前に5回の塞栓術と放射線治療を行っていたが,両症例とも再出血した.症例4,5は巨大なAVMで,根治的治療が困難と脳外科より判断されていた症例であった.全例とも妊娠前および妊娠後中に根治的治療が未施行のため帝王切開を行い,生児を得ることができた

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Other Link： http://search.jamas.or.jp/link/ui/2006286791

Language：Japanese   Publisher：日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=437616

Language：Japanese   Publisher：(株)診断と治療社  

63歳女性.患者は頸部左側の腫瘤増大で近医を受診,悪性腫瘍遠隔転移を疑われ紹介受診となった.所見では,左鎖骨上窩に母指頭大の硬い腫瘤が触知でき,穿刺吸引細胞診ではclass V(adenocarcinoma),子宮腟部の前腟円蓋には4〜5cm大の易出血性腫瘤が認められた.一方,MRIならびにCTでは子宮頸部右側から腹側に5cm大の腫瘤を認め,頸部から骨盤内までの著明なリンパ節腫大が確認された.以上,これらより子宮頸部腺癌IVb期と診断し,Weekly Paclitaxel(T)-Aclarubicin(A)-Carboplatin(J)(weekly TAJ)療法を開始した.その結果,1コース終了後,子宮頸部病変は33%,左鎖骨上窩リンパ節は64%減少し,他の全ての病変も縮小傾向を認め,2コース終了後には子宮頸部病変は89%減少し,各リンパ節腫大は消失した.そして,4コース終了後の治療効果判定ではclinical CRとなり,以後,準広汎子宮全摘術,両側付属器摘出術,傍大動脈ならびに骨盤リンパ節郭清術を施行することになった

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Other Link： http://search.jamas.or.jp/link/ui/2006103851

Language：Japanese   Publisher：新潟産科婦人科学会  

35歳女.体外受精にて妊娠が成立した.妊娠9週に切迫流産にて,双胎管理目的で受診となり,妊娠24週に子宮頸管長17mmと短縮が認められ,切迫早産管理目的で入院となった.所見では,小球性低色素性貧血を認め,また妊娠24週には甲状腺腫も認められ,甲状腺機能亢進症と診断された.妊娠28週頃より前頸部痛を訴える様になり,上部消化管内視鏡にて食道裂孔ヘルニア,逆流性食道炎が指摘された.その後,妊娠32週頃より正球性正色素性貧血の他に白血球減少,血小板減少,汎血球減少を認める様になった.妊娠33週0日に帝王切開術が施行され,産褥5日に貧血の進行を認め,9日に骨髄穿刺が施行された.葉酸欠乏性巨赤芽球性貧血と診断されたが,徐々に回復し,退院後より甲状腺機能も回復傾向に,目下は経過観察中である

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Language：Japanese   Publisher：新潟産科婦人科学会  

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=436293

Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(株)先端医学社  

骨粗鬆症に関与する「骨強度」は「骨密度(骨量)」と「骨質」の両者を反映するものとされている.エストロゲンは骨密度のみでなく,骨質の改善にも関与する.「骨質」に注目されはじめた今日,エストロゲンの骨粗鬆症に対する効果が今後再び注目されるかもしれない.しかし,WHIの報告以降,ホルモン補充療法(HRT)はできる限り短期間で低用量を用いることが推奨されている.また,HRTにかわる新たな骨粗鬆症治療薬が登場してきた.骨粗鬆症の治療・予防に対するHRTは,女性一人一人のリスク因子や更年期障害の治療の必要性を考慮して選択すべきであろう(著者抄録)

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Other Link： http://search.jamas.or.jp/link/ui/2005060701

Language：Japanese   Publisher：新潟産科婦人科学会  

子宮鏡下手術26例(平均45.2歳)を対象とした.症状は過多月経15例,不正性器出血4例,原発不妊1例,検査目的7例で,疾患は子宮内膜ポリープ15例,子宮筋腫10例,子宮筋腫+子宮内膜ポリープ1例であった.手術は腫瘤切除のみが18例で,内膜破壊術併用は8例であった.手術時間は平均25.7分で,出血量は全例少量であった.入院期間は24例が3日で,他は本人希望の4日と,慢性心疾患合併例の8日であった.子宮穿孔や水中毒などの合併症,後遺症はなかった.子宮筋腫では1例を除いて有症状であったが,子宮ポリープは6例が無症状で,最大径はそれぞれ32.0mm,20.6mm,手術時間は36.8分,17.5分と有意差を認めた.子宮筋腫例のうち有茎性は5例,無茎性は6例で,内膜破壊術併用は各々2例,3例,腫瘍最大径は各々38.0mm,27.0mm,手術時間は各々27.2分,44.8分であった.断面積で60%が埋没していた1例に腫瘍残存を認めたが,過多月経は消失していた

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Language：Japanese   Publisher：新潟産科婦人科学会  

恥骨尿道靱帯補強術(TVT手術)を行った6例(55-83歳女性)について検討を行った.患者の主訴は全例が性器脱で,4例は尿失禁が先行していた.全例で複数の経腟分娩歴・膀胱瘤を認めた.また,術前に子宮脱リングを用いたが,尿失禁は不変か悪化した.手術は,4例で前腟壁形成の併用,1例で中央腟閉鎖術と併用,1例で子宮全摘術および前後腟壁形成術と併用した.5例では3日目に残尿が100ml以下となり,術後2-11日目に退院となった.術後,尿失禁,尿道過可動,後部膀胱尿道角,内因性尿道括約筋などは改善傾向を認めた

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Language：Japanese   Publisher：日本産科婦人科学会-東北連合地方部会  

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Language：Japanese   Publisher：日本産科婦人科学会-東北連合地方部会  

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